Pancreatic Cancer: Causes and Signs

Pathogenesis (disease development)

More than 95% of pancreatic cancers are ductal adenocarcinoma. This arises from malignant degeneration of exocrine pancreatic tissue (production of digestive enzymes). The pathogenesis is not yet fully understood. It is assumed that, as in the case of other malignant neoplasms comparable to colorectal carcinoma, mutations (changes in genetic material) gradually lead to the development of the carcinoma via lesions. Besides pancreatic intraepithelial neoplasia (PanIN), this is mainly intraductal papillary mucinous neoplasia (IPMN), which is comparable to intestinal polyps. In many cases, a mutation in the K-RAS and CDKN2A genes can be detected.

Etiology (Causes)

Biographic Causes

  • Genetic burden
    • Parents, grandparents as in familial breast cancer (breast cancer)/ovarian cancer syndrome (ovarian cancer syndrome; autosomal dominant inherited mutations in Breast cancer (BRCA) genes 1 and 2) or familial colon cancer (colon cancer)
    • First-degree relationship of patients with pancreatic cancer: in one relative to 4.6 times, in two to 6.4 times and in three even to 32 times
    • More than 5% of all patients with pancreatic ductal carcinoma have mutations in 6 genes (CDKN2A, TP53, MLH1, BRCA1 BRCA2, PALB2)
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: ATM, CLPTM1, NR5A2.
        • SNP: rs1801516 in the gene ATM
          • Allele constellation: AA (2.76-fold).
        • SNP: rs401681 in the gene CLPTM1
          • Allele constellation: CT (1.19-fold).
          • Allele constellation: TT (1.42-fold)
        • SNP: rs9543325 in an intergenic region.
          • Allele constellation: CT (1.37-fold).
          • Allele constellation: CC (1.37-fold)
        • SNP: rs3790844 in gene NR5A2
          • Allele constellation: CT (0.77-fold).
          • Allele constellation: CC (0.59-fold)
    • Genetic diseases
      • Familial adenomatous polyposis (FAP; synonym: Familial polyposis) – is an autosomal dominant inherited disease. This leads to the occurrence of a large number (> 100 to thousands) of colorectal adenomas (polyps). The probability of malignant degeneration is almost 100% (on average from the age of 40); furthermore, the risk of pancreatic ductal carcinoma is increased 4-5 times compared to the general population.
      • Hereditary breast and ovarian cancer (breast and ovarian cancer): the risk of pancreatic ductal carcinoma compared to the general population is increased 4-5-fold.
      • Hereditary pancreatitis – genetic disease with autosomal dominant inheritance; prevalence (disease incidence) of pancreatic cancer with a lifetime risk of 39% at 0.3/100,000
      • MEN-1 syndrome (MEN = multiple endocrine neoplasia) – genetic disorder characterized by both autosomal dominant and sporadic inheritance; syn- or metachronous occurrence of tumors preferably of the pituitary gland (pituitary gland), parathyroid glands, endocrine pancreas (portion of the pancreas that produces the hormone insulin), and duodenum (duodenum).
      • Von Hippel-Lindau syndrome (VHL; synonym: retino-cerebellar angiomatosis) – genetic disease with autosomal dominant inheritance from the group of forms known as phakomatoses (group of diseases with malformations in the area of the skin and nervous system); symptoms: benign angiomas (benign vascular malformations), mainly in the area of the retina (retina) and cerebellum.
      • HNPCC (Engl. heredetery non-polyposis colorectal cancer; hereditary colorectal cancer without polyposis, also known as “Lynch syndrome“) – genetic disease with autosomal dominant inheritance; associated with early-onset colorectal cancer (cancer of the colon or rectum) and possibly other tumor diseases.
      • Peutz-Jeghers syndrome (synonyms: Hutchinson-Weber-Peutz syndrome or Peutz-Jeghers hamartosis) – genetic disorder with autosomal dominant inheritance; associated with gastrointestinal polyposis (occurrence of numerous polyps in the gastrointestinal tract) with characteristic pigmented patches on the skin (especially in the middle of the face) and mucous membranes; clinical picture: Recurrent (recurrent) colicky abdominal pain; iron deficiency anemia; blood accumulation on stool; possible complications: Ileus (intestinal obstruction) due to invagination of a polyp-bearing intestinal segment; prevalence of pancreatic cancer with a lifetime risk of 17% at 0.25/100,000
      • Sporadic pancreatic cancer in the family: the risk of pancreatic ductal carcinoma compared with the normal population is increased 18-fold in 2 sufferers and 57-fold in 3 sufferers or more.
  • Blood group – blood group A (2.01 times increased risk; Germany).
  • Ethnic origin – belonging to the black population.

Behavioral causes

  • Nutrition
    • High consumption of red meat, i.e., muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat; this is classified by the World Health Organization (WHO) as “probably carcinogenic to humans,” i.e., carcinogenicMeat and sausage products are classified as so-called “definite group 1 carcinogens” and are thus comparable (qualitatively but not quantitatively) to the carcinogenic (cancer-causing) effect of tobacco smoking. Meat products include products whose meat component has been preserved or improved in flavor by processing methods such as salting, curing, smoking, or fermenting: Sausages, sausage products, ham, corned beef, jerky, air-dried beef, canned meat.
    • Smoked and cured foods and foods rich in nitrates and nitrites.
    • Benzo(a)pyrene is formed during toasting and charcoal grilling. It is considered a probable risk factor for pancreatic cancer (cancer of the pancreas). It is found in all grilled, smoked or burnt foods. Cigarette smoke also contains benzo(a)pyrene, which in turn can lead to bronchial carcinoma.
    • Nitrate is a potentially toxic compound: Nitrate is reduced to nitrite in the body by bacteria (saliva/stomach). Nitrite is a reactive oxidant that reacts preferentially with the blood pigment hemoglobin, converting it to methemoglobin. Furthermore, nitrites (also contained in cured sausage and meat products and ripened cheese) form nitrosamines with secondary amines (contained in meat and sausage products, cheese and fish), which have genotoxic and mutagenic effects. Among other things, they promote the development of pancreatic cancer. The daily intake of nitrate is usually about 70% from the consumption of vegetables (lamb’s lettuce, lettuce, green, white and Chinese cabbage, kohlrabi, spinach, radish, radish, beet), 20% from drinking water (nitrogen fertilizer) and 10% from meat and meat products and fish.
  • Pleasure food consumption
    • Alcohol
    • Tobacco (smoking); passive smoking
  • Overweight (BMI ≥ 25; obesity).
    • Obesity at age 16-19 years (transition age) increases the rate of pancreatic cancer by 3.8-fold
    • Increasing BMI from 25 to 35 increases tumor risk by about 74
    • Obesity and high fasting insulin levels (per standard deviation (44.4 pmol/l) upward → increase in tumor risk by 66%) (especially men).

Disease-related causes

  • Chronic pancreatitis, longstanding (pancreatitis); incidence (frequency of new cases): relative risk 2.3-18.5%; cumulative incidence 1.1% (after 5 years), 1.8% (after 10 years), 4% (after 20 years).
  • Diabetes mellitus type 2 (diabetes).
  • Familial atpic multiple birthmark and melanoma syndrome (FAMMM syndrome) – in addition to the occurrence of nevi (skin moles) and increased risk of melanoma, also clustered occurrence of pancreatic cancer.
  • Periodontitis with:

Laboratory diagnoses – laboratory parameters considered independent risk factors.

  • Fasting glucose (synonyms: Blood glucose level, blood glucose (BG); blood glucose) – increase in glucose concentration by 10 mg/dl (0.555 mmol/l) increases pancreatic cancer risk by 14
  • Fasting insulin-high fasting insulin levels and obesity (per standard deviation (44.4 pmol/l) upward → 66% increase in tumor risk) (mainly men)

Surgeries

Environmental exposure – intoxications (poisonings) risks not conclusively confirmed.

  • Ingestion of nitrosamines
  • Chlorinated hydrocarbons
  • Chromium/chromium compounds
  • Electromagnetic fields
  • Fungicides
  • Herbicides
  • Fuel vapors
  • Pesticides