Pancreatic carcinoma

Pancreatic carcinoma is a malignant tumour arising from the exocrine part of the pancreas, most often it is a solid adenocarcinoma, less often cystic tumours (< 5%). The origin of the malignant elements is mainly from the epithelium of the pancreatic ducts, approximately one percent are from acini cells. Macroscopically, it is a resistant nodule of a yellowish colour with central necrosis or vascularisation.

In addition to its increasing incidence in the population, which has not yet been satisfactorily explained, it has a high mortality rate, even in cases of early detection of malignancy. It affects men slightly more often than women. In recent years, it has been ranked fourth in terms of mortality (after lung cancer, colorectal cancer and breast cancer). Only 4% of patients live to five years after diagnosis, and the majority do not live beyond one year. Nowadays, the disease is often diagnosed at an advanced stage. Clinically, it is often asymptomatic for a long time or the symptoms are so subtle that they do not attract the attention of the patient or the treating physician. The tumour markers commonly used in the diagnosis does not have significant diagnostic value as they are not specific for pancreatic cancer.

Age
It represents the strongest risk factor. Under the age of 30, the disease is rare, after this age the incidence rises sharply and the peak is reached in seventh and eighth decades.

Smoking
A significant risk factor for the development of the disease, it is associated with a two- to threefold increase in the risk of malignancy. The mechanism is based on the action of tobacco N-nitrosamines directly on target cells or by their secretion into bile with possible reflux into the pancreatic ducts. Passive smoking has not been confirmed as a risk factor.

Alcohol
Alcohol is currently confirmed only as an indirect risk factor for developing cancer. It is possible through its ability to induce chronic pancreatitis, which is a recognised as an endogenous risk factor.

Dietary factors
High intake of meat, cholesterol and fried foods are risk factors as well. On the other hand, vegetables, fruits, fibre, vitamin C and other antioxidants prevent the development of cancer.

Chronic pancreatitis
Chronic inflammation induces genetic changes in the tissue and the simultaneous healing process exposes the defective cells to growth factors produced by activated macrophages. These are TNF-α, IL-1, IL-6, IL-8, EGF, PDGF, TGF-α, TGF-β (transforming growth factor). Growth factors induce cell proliferation (they accelerate cell division and thus increase the likelihood of stabilizing genetic mutations in the cell population), angiogenesis and desmoplastic response. TGF-α inhibits the processes leading to apoptosis through activation of NF-κB (nuclear factor kappa B), which acts as a transcription factor but also stimulates the production of reactive nitrogen oxide, cyclooxygenase-2 (COX-2) and induces IL-8 expression. COX-2 increases the amount of anti-inflammatory prostaglandins, which are able to facilitate cell proliferation and angiogenesis during inflammation and carcinoma, in addition it inhibits apoptosis. Reactive oxygen and nitrogen forms (produced by neutrophil granulocytes or generated by COX-2 activity) are directly related to DNA structural defects. People with chronic pancreatitis have a 16 times higher risk of developing pancreatic cancer compared to the healthy population. The time interval between the diagnosis of chronic pancreatitis and pancreatic cancer is 6-13 years. The increase in risk is mainly influenced by the duration of chronic pancreatitis and smoking.

Diabetes mellitus
The risk is represented by type 2 diabetes melitus, what is insulin resistance of targer cells. In this situation, there is even an overproduction of insulin. Tumour cells often overexpress the insulin receptor. Its overactivation stimulates, besides, mitosis.

Familial burden
This refers to families in which a mutation in a proto-oncogene, mismatch repair gene or tumour suppressor gene is present and inherited. Typical examples include mutations in the p53 gene (Li Fraumeni syndrome), MMR genes (Lynch syndrome), inherited BRCA2 mutations, and a syndrome that links pancreatitis, diabetes mellitus and pancreatic cancer to a previously unidentified gene locus.

Hereditary pancreatitis
An autosomal dominantly inherited disorder usually caused by a defect in the trypsinogen gene. Those so affected have a 40 times higher risk of developing cancer than the healthy population.

Other
Other risk factors include mainly post gastrectomy status, cholelithiasis, cholecystectomy.

Molecular genetic mechanisms of developing pancreatic cancer
For a text on the genetic background of pancreatic cancer, see Molecular genetic mechanisms of pancreatic cancer.

Clinical symptomatology
Clinically, the carcinoma may be asymptomatic until late stages; symptoms may often be based on the location of the tumour - obstructive icterus (in carcinomas of the head of the pancreas), vomiting in duodenal obstruction, epigastric pain with propagation to the back, weight loss, inappetence, indigestion (pancreatic insufficiency with steatorrhea), thrombophlebitis migrans of the veins of the lower limbs (paraneoplastic). In the late stages, portal hypertension with the development of oesophageal varices or haemorrhagic ascites with spreading to the peritoneum.

Diagnostics
For diagnosis, imaging methods such as ultrasonography (USG), endoscopic ultrasonography (EUS), CT, PET, ERCP are used today. Methods are constantly being sought to detect cancer at an early stage. Peripheral blood testing for tumour markers is offered. Elevated carcinoembryonic antigen (CEA), alpha fetoprotein (AFP) and pancreatic oncofetal antigen (POA) can be detected but are not specific. For this reason, part of the scientific work is focused on the search for an ideal marker that can be obtained from peripheral blood to avoid invasive biopsy or ERCP. Currently, there are procedures that can detect early K-ras gene mutations in circulating metastatic cells (present in the peripheral blood) or detect mutations of the same gene in tumour epithelial cells that enter the stool with the pancreatic juices.

Biological behaviour
This tumour is characterised by perineural spread (penetration into nerves - usually splanchnic nerves), which is a source of severe pain. In more advanced stages, it can also spread into the surrounding organs (bile ducts, duodenum, blood vessels), spreading to the peritoneum is common. It metastasizes to local lymph nodes (nodi lymphatici hepatici - from the head of the pancreas, nodi lymphatici coeliaci et pancreaticolienales - body and tail), haematogenously into the liver, later into the lungs and bones.

Surgical treatment
Surgical procedures can be curative - resection or palliative, contraindication to resection is significant tumor penetration into large vessels (v. + a. mesenterica superior, v. portae, even their partial resection is possible) or metastases into the liver and spread to the peritoneum. Despite advanced imaging methods, tumor penetration into blood vessels is often detected only by the surgeon peroperatively. Nerve penetration (usually into the splanchnic nerves) cannot be detected.

curative interventions
the aim is to cure the patient, they are divided according to the tumour localization and extent of affected area, after resection it is necessary to monitor the exo- and endocrine functions of the pancreas and, if necessary, to provide substitution with pancreatic enzymes and insulin


 * 1) resection of the pancreatic cauda (resection of the parenchyma with tumour + regional lymphadenectomy + resection of the duodenum, possibly splenectomy),
 * 2) partial duodenopancreatectomy (Whipple resection),
 * 3) total duodenopancreatectomy with gastrojejunoanastomosis.

palliative interventions
in advanced tumors, solves life-threatening complications


 * 1) when obstructive icterus - biliodigestive anastomosis (hepatico-jejunoanastomosis),
 * 2) when duodenal stenosis - gastro-jejuno anastomosis,
 * 3) when unquenchable pain - sympathectomy.

Radio and chemotherapy
They generally have very little efficacy, these therapies are palliative in most cases. Of the cytostatics, gemcitabine (a nucleoside analogue, also tried in combination with other agents) is the standard treatment, but even then patient survival is within a few months.

Conclusion
In conclusion, it is important to say that the prognosis of this disease is very poor. The chance to improve it or prolong the patient's life is to catch the malignancy early, which is still not possible due to asymptomaticity. It is important for physicians to identify patients at risk (over 65 years of age, recurrent chronic pancreatitis, smokers, obese, ...) and pay special attention to them.

Summary video
https://www.youtube.com/watch?v=lQAqPlOAYMM

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