|Classification and external resources|
Pancreatic cancer occurs when cancer cells develop from the pancreas, a glandular organ located behind the stomach. Signs and symptoms of pancreatic cancer may include abdominal or back pain, yellow skin, unexplained weight loss, light colored stools, dark urine and loss of hunger. Early on there are often no symptoms. Symptoms that are specific enough to suspect pancreatic cancer often do not appear until the disease is already in an advanced stage. By the time of diagnosis the cancer has usually spread to other parts of the body.
Risk factors include: smoking, obesity, diabetes, and certain rare genetic conditions including: multiple endocrine neoplasia type 1 and hereditary nonpolyposis colon cancer among others. Smoking is the cause of about 20% of cases while 10% of cases are inherited from a person's parents. Infiltrating ductal adenocarcinoma is the most common type of pancreatic cancer, making up 90% of cases. It arises within the part of the pancreas that makes digestive enzymes, known as the exocrine pancreas. One to two percent arise from islet cells, and are classified as neuroendocrine tumors. There are also a number of other types of pancreatic cancer. Diagnosis is usually based on a combination of imaging tests such as ultrasound and computer tomography, blood tests such as CEA and CA 19-9 and biopsy. This allows the disease to be divided into five stages.
The most important form of prevention is to cease smoking, after which the risk of the disease returns to normal within 20 years. Other recommendations include limiting alcohol intake and eating a healthy diet. Screening the general population has not been found to be effective. For people affected by the disease treatments may include: surgery, radiation therapy, chemotherapy, or a combination of treatments. Recommendations are partly based on the cancer stage. Surgery may be done in an effort to cure the disease or to try to improve quality of life without trying to cure. Pain management and medications to improve digestion are sometimes needed. Early palliative care is recommended even in those who are receiving active treatment.
In 2012 pancreatic cancer caused 330,000 deaths globally, the seventh most common cause of deaths due to cancer. In the United States it is the fourth most common cause of deaths due to cancer. The disease occurs more often in the developed world, where 68% of new cases occur in 2012. It often has poor outcomes with the average one and five year survival rate being 25% and 5% respectively. In localized disease where the cancer is small (< 2 cm) the 5-year survival is approximately 20%. For those with neuroendocrine cancer the survival at five years is better at 65%. In the United States, as of 2006, the economic costs of pancreatic cancer are estimated at $8.6 billion.
- 1 Signs and symptoms
- 2 Risk factors
- 3 Diagnosis
- 4 Pathophysiology
- 5 Prevention
- 6 Management
- 7 Prognosis
- 8 Epidemiology
- 9 Research
- 10 See also
- 11 References
- 12 External links
Signs and symptoms
Early pancreatic cancer often does not cause symptoms, and the later symptoms are usually nonspecific and varied. Therefore, pancreatic cancer is often not diagnosed until it is advanced. Common symptoms include:
- Pain in the upper abdomen that typically radiates to the back (seen in carcinoma of the body or tail of the pancreas)
- Heartburn - acid stomach
- Poor appetite or nausea and vomiting
- Diarrhea, loose stools.
- Significant weight loss (cachexia)
- Painless jaundice (yellow tint to whites of eyes (sclera) or yellowish skin, possibly in combination with darkened urine) when a cancer of the head of the pancreas (75% of cases) obstructs the common bile duct as it runs through the pancreas. This may also cause pale-colored stool and steatorrhea. The jaundice may be associated with itching as the salt from excess bile can cause skin irritation.
- Trousseau syndrome, in which blood clots form spontaneously in the portal blood vessels, the deep veins of the extremities, or the superficial veins anywhere on the body, may be associated with pancreatic cancer.
- Pulmonary embolisms due to pancreatic cancers producing blood clotting chemicals.
- Diabetes mellitus, or elevated blood sugar levels. Many patients with pancreatic cancer develop diabetes months to even years before they are diagnosed with pancreatic cancer, suggesting new onset diabetes in an elderly individual may be an early warning sign of pancreatic cancer.
- Clinical depression has been reported in association with pancreatic cancer, sometimes presenting before the cancer is diagnosed. However, the mechanism for this association is not known.
- Symptoms of pancreatic cancer metastasis. Typically, pancreatic cancer first metastasizes to regional lymph nodes, and later to the liver or to the peritoneal cavity and, rarely, to the lungs; it rarely metastasizes to bone or brain.
- Age, gender and race. The risk of developing pancreatic cancer increases with age. Most cases occur after age 65, while cases before age 40 are uncommon. The disease is somewhat more common in men than women, and in the United States is over 1.5 times more common in African Americans, though incidence in Africa is low.
- Smoking. Cigarette smoking has a risk ratio of 1.74 with regard to pancreatic cancer; a decade of nonsmoking after heavy smoking is associated with a risk ratio of 1.2.
- Family history: 5–10% of pancreatic cancer patients have a family history of pancreatic cancer. The genes have not been identified. Pancreatic cancer has been associated with the following syndromes: autosomal recessive ataxia-telangiectasia and autosomal dominantly inherited mutations in the BRCA2 gene and PALB2 gene, Peutz-Jeghers syndrome due to mutations in the STK11 tumor suppressor gene, hereditary non-polyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, and the familial atypical multiple mole melanoma-pancreatic cancer syndrome (FAMMM-PC) due to mutations in the CDKN2A tumor suppressor gene. There may also be a history of familial pancreatitis.
- Chronic pancreatitis has been linked, but is not known to be causal. The risk of pancreatic cancer in individuals with familial pancreatitis is particularly high.
- Diabetes mellitus is both a risk factor for pancreatic cancer, and, as noted earlier, new onset diabetes can be an early sign of the disease.
- Helicobacter pylori infection
- Gingivitis or periodontal disease
- Diets low in vegetables and fruits.
- Diets high in red meat. Processed meat consumption is positively associated with pancreatic cancer risk, and red meat consumption was associated with an increased risk of pancreatic cancer in men.
- Diets high in sugar-sweetened drinks (soft drinks). In particular, limited epidemiological studies link the common soft drink sweetener fructose with growth of pancreatic cancer cells.
- Partial gastrectomy
It is controversial whether alcohol consumption is a risk factor for pancreatic cancer. Overall, the association is consistently weak and the majority of studies have found no association. Although drinking alcohol excessively is a major cause of chronic pancreatitis, which in turn predisposes to pancreatic cancer, chronic pancreatitis associated with alcohol consumption is less frequently a precursor for pancreatic cancer than other types of chronic pancreatitis.
Some studies suggest a relationship, the risk increasing with increasing amount of alcohol intake. The risk is greatest in heavy drinkers, mostly on the order of four or more drinks per day. There appears to be no increased risk for people consuming up to 30g of alcohol a day, which is approximately 2 alcoholic beverages/day, so most people who take alcohol do so at a level that "is probably not a risk factor for pancreatic cancer". A pooled analysis concluded, "Our findings are consistent with a modest increase in risk of pancreatic cancer with consumption of 30 or more grams of alcohol per day".
Several studies caution that their findings could be due to confounding factors. Even if a link exists, it "could be due to the contents of some alcoholic beverages" other than the alcohol itself. One Dutch study even found that drinkers of white wine had lower risk.
Pain is present in 80% to 85% of patients with locally advanced or advanced metastatic disease. The pain is usually felt in the upper abdomen as a dull ache that radiates straight through to the back. It may be intermittent and made worse by eating. Weight loss can be profound; it can be associated with anorexia, early satiety, diarrhoea, or steatorrhea. Jaundice is often accompanied by pruritus and dark urine. Painful jaundice is present in approximately one-half of patients with locally unresectable disease, while painless jaundice is present in approximately one-half of patients with a potentially resectable and curable lesion.
The initial presentation varies according to location of the cancer. Malignancies in the pancreatic body or tail usually present with pain and weight loss, while those in the head of the gland typically present with steatorrhea, weight loss, and jaundice. The recent onset of atypical diabetes mellitus, a history of recent but unexplained thrombophlebitis (Trousseau sign), or a previous attack of pancreatitis are sometimes noted. Courvoisier sign defines the presence of jaundice and a painlessly distended gallbladder as strongly indicative of pancreatic cancer, and may be used to distinguish pancreatic cancer from gallstones. Tiredness, irritability and difficulty eating because of pain also exist. Pancreatic cancer is often discovered during the course of the evaluation of aforementioned symptoms.
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. When a cutoff above 37 U/mL is used, this marker has a sensitivity of 77% and specificity of 87% in discerning benign from malignant disease. CA 19-9 might be normal early in the course, and could be elevated because of benign causes of biliary obstruction. Imaging studies, such as computed tomography (CT scan) and endoscopic ultrasound (EUS) can be used to identify the location and form of the cancer. The definitive diagnosis is made by an endoscopic needle biopsy or surgical excision of the radiologically suspicious tissue. Endoscopic ultrasound is often used to visually guide the needle biopsy procedure. Nonetheless, pancreatic cancer is usually staged using a CT scan. In fact, a histologic diagnosis is not usually required for resection of the tumor, rather histologic analysis helps determine which chemotherapeutic regimen to start.
The development of pancreatic cancer may involve the over-expression of oncogenes, inactivation of tumor suppressor genes or the deregulation of various signaling proteins. Mutations leading to carcinoma may be accelerated by genetic or environmental factors and other risk factors already described. Specific mutations vary among and even within the cyto-histologic categories discussed below.
Exocrine pancreas cancers
The most common form of pancreatic cancer (ductal adenocarcinoma) is typically characterized by moderately to poorly differentiated glandular structures on microscopic examination. Pancreatic cancer has an immunohistochemical profile that is similar to hepatobiliary cancers (e.g. cholangiocarcinoma) and some stomach cancers; thus, it may not always be possible to be certain that a tumour found in the pancreas arose from it.
The genetic events that cause ductal adenocarcinoma have been well characterized. The most common are KRAS mutations (96%), CDKN2A mutations/deletions (75%), TP53 mutations (55%), SMAD4 deletions/mutations (50%), and SWI/SNF mutations/deletions (35%).
Pancreatic carcinoma is thought to arise from progressive tissue changes. Three types of precancerous lesion are recognised: pancreatic intraepithelial neoplasia – a microscopic lesions of the pancreas, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms both of which are macroscopic lesions. The cellular origin of these lesions is debated.
Other exocrine cancers include adenosquamous carcinomas, signet ring cell carcinomas, hepatoid carcinomas, colloid carcinomas, undifferentiated carcinomas, and undifferentiated carcinomas with osteoclast-like giant cells.
Pancreatic cystic neoplasms
Pancreatic cystic neoplasms are a broad group of pancreas tumors that have varying malignant potential.[discuss]
Pancreatic neuroendocrine tumors
Endocrine pancreatic tumors have been variously called islet cell tumors, pancreas endocrine tumors (PETs), and pancreatic neuroendocrine tumors (PNETs). The annual clinically recognized incidence is low, about five per one million person-years. However, autopsy studies incidentally identify PETs in up to 1.5% most of which would remain inert and asymptomatic.
The majority of PNETs are usually categorized as benign but the definition of malignancy in pancreas endocrine tumors has been ambiguous. A small subset of endocrine pancreatic tumors are incontrovertible pancreatic endocrine cancers, that make up about 1% of pancreas cancers. Low- to intermediate-grade neuroendocrine carcinomas of the pancreas may be called islet cell tumors. Some sources have also termed these pancreatic carcinoid, a practice that has sometimes been strongly condemned. Definitional migration has caused some complexity of PNET classification, which has adversely affected what is known about the epidemiology and natural history of these tumors. It is probable that some of these tumors have been included in ICD-O-3 histology classifications 8240–8245, in that they were labeled pancreatic carcinoid tumours but most islet cell carcinomas have been coded as ICD-O-3 system 8150–8155.
The more aggressive endocrine pancreatic cancers are known as pancreatic neuroendocrine carcinomas (PNEC). Similarly, there has likely been a degree of admixture of PNEC and extrapulmonary small cell carcinoma.
The ACS recommends keeping a healthy weight, and increasing consumption of fruits, vegetables, and whole grains, while decreasing red meat intake, although there is no consistent evidence this will prevent or reduce pancreatic cancer specifically. In 2006, a large prospective cohort study of over 80,000 subjects failed to prove a definite association. The evidence in support of this lies mostly in small case-control studies.
A long-term study found that people who consumed in the range of 300 to 449 international units (IU) of vitamin D daily had a 43% lower risk of pancreatic cancer than those who took less than 150 IU per day; 150 IU is appreciably less than what was then, or is now, recommended. The World Health Organization (WHO) International Agency for Research on Cancer (IARC) concluded that there were insufficient studies in pancreatic cancer. Furthermore, while the IARC found evidence for an inverse association between vitamin D and colorectal cancer to be persuasive, it found evidence for a causal link to be limited, and also found that randomized controlled trials (RCTs) were inconclusive. Taking too much vitamin D may be harmful. Poor general diet, obesity, and relative physical inactivity can be risk factors in some cancers, so the role of vitamin D itself is not certain.
A Harvard study from 2007 showed a modest inverse trend between blood circulation of B vitamins, such as B12, B6, and folate and pancreatic cancer incidence, but not when the vitamins were ingested in tablet form. However, the results of a meta-analysis of randomized trials by Rothwell and colleagues indicate that taking a daily low-dose aspirin regimen for more than five years decreases the risk of developing pancreatic adenocarcinoma (ductal pancreatic cancer) by 75%.
People who may have a high risk of pancreatic cancer due to a family history can be followed, but there is no consensus on what constitutes optimal monitoring.
Treatment of pancreatic cancer depends on the stage of the cancer. Although only localized cancer is considered suitable for surgery with curative intent at present, only 20% of cases present with localised disease at diagnosis. Surgery can also be performed for palliation, if the malignancy 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.
The Whipple procedure is the most common attempted curative surgical treatment for cancers involving the head of the pancreas. This procedure involves removing the pancreatic head and the curve of the duodenum together (pancreato-duodenectomy), making a bypass for food from stomach to 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 patient is likely to survive major surgery and if the cancer is localized without invading local structures or metastasizing. It can, therefore, be performed in only the minority of cases.
Cancers of the tail of the pancreas can be resected using a procedure known as a distal pancreatectomy. Recently, localized cancers of the pancreas have been resected using minimally invasive (laparoscopic) approaches.
After surgery, adjuvant chemotherapy with gemcitabine has been shown in several large randomized studies to significantly increase the 5-year survival (from approximately 10 to 20%), and should be offered if the patient is fit after surgery (Oettle et al. JAMA 2007, Neoptolemos et al. NEJM 2004, Oettle et al. ASCO proc 2007).
Those with inoperable pancreatic cancer may have significant abdominal pain. A celiac plexus block (CPB), which destroys the nerves that transmit pain from the abdomen, is a safe and effective way to reduce the pain. CPB generally reduces the need to use pain killers like opioids, which have significant negative side effects.
Principles of radiation therapy in pancreas adenocarcinoma are reviewed extensively in guidelines by the National Comprehensive Cancer Network. Radiation can be considered in several situations. One situation is the addition of radiation therapy after potentially curative surgery. Groups in the US have been more apt to use adjuvant radiation therapy than groups in Europe.
In people not suitable for resection with curative intent, palliative chemotherapy may be used to improve quality of life and gain a modest survival benefit. Gemcitabine was approved by the United States Food and Drug Administration in 1998, after a clinical trial reported improvements in quality of life and a 5-week improvement in median survival duration in patients with advanced pancreatic cancer. This marked the first FDA approval of a chemotherapy drug primarily for a nonsurvival clinical trial endpoint. Gemcitabine is administered intravenously on a weekly basis.
- Watchful waiting: incidentally identified small tumors, for example on a computed tomography (CT) scan performed for other purposes, may conceptually not always need intervention, but criteria for watchful waiting are unclear.
- Surgery: tumors within the pancreas only (localized tumors), or with limited metastases, may be removed. For localized tumors, the surgical procedure is much less extensive than the types of surgery used to treat pancreatic adenocarcinoma.
- Hormone therapy: if the tumor is not amenable to surgical removal and is causing symptoms by secreting functional hormones, a synthetic hormone analog medication, octreotide, may lessen the symptoms, and sometimes also slows tumor growth.
- Radiation therapy: occasionally used if there is pain due to anatomic extension, such as metastasis to bone.
- Radiolabeled hormone: some PNETs absorb a hormone called norepinephrine and these may respond to nuclear medicine medication, radiolabeled MIBG therapy (or, experamentally, other hormones), given intravenously.
- Chemotherapy and targeted medication for PNETs receive Wikipedia discussion in the relevant section of that article.
Exocrine pancreatic cancer (adenocarcinoma and less common variants) typically has a poor prognosis, partly because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis.
Pancreatic cancer may occasionally result in diabetes. Insulin production is hampered, and it has been suggested the cancer can also prompt the onset of diabetes and vice versa. It can be associated with pain, fatigue, weight loss, jaundice, and weakness. Additional symptoms are discussed above.
For pancreatic cancer:
- For all stages combined, the 1-year relative survival rate is 25%, and the 5-year survival is estimated as less than 5%  to 6%.
- For local disease, the 5-year survival is approximately 20%.
- For locally advanced and for metastatic disease, which collectively represent over 80% to 85-90% of individuals, the median survival is about 10 and 6 months, respectively. Without active treatment, metastatic pancreatic cancer has a median survival of 3–5 months; complete remission is very rare.
Outcomes with pancreatic endocrine tumors, many of which are benign and completely without clinical symptoms, are much better, as are outcomes with symptomatic benign tumors; even with actual pancreatic endocrine cancers, outcomes are rather better, but variable.
Globally, as of 2012, pancreatic cancer resulted in 330,000 deaths, up from 310,000 in 2010 and 200,000 in 1990. In 2010, an estimated 43,000 people in the US were diagnosed with pancreas cancer and almost 37,000 died from the disease. Pancreatic cancer has one of the highest fatality rates of all cancers, and is the fourth-highest cancer killer among both men and women worldwide. Although it accounts for only 2.5% of new cases, pancreatic cancer is responsible for 6% of cancer deaths each year.
- Gastrointestinal cancer
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