pancreatic cancer

Introduction

“pancreatic cancer” usually refers to adenocarcinoma of the exocrine pancreatic ducts which accounts for 85% of all pancreatic neoplasia
95% of all malignant pancreatic tumours arise from the exocrine pancreas
endocrine pancreas may give rise to pancreatic neuroendocrine tumours such as islet cell tumours

mutations in the KRAS gene are the major driver of pancreatic cancer
- the resulting protein controls multiple signaling pathways involved in cell growth and survival
- attempts to inhibit KRAS as a Rx results in a group of genes upstream of KRAS, called ERBB becoming upregulated hence research is looking at combining KRAS inhibition (eg. MRTX1133) and ERBB inhibition (eg. Afatinib) as a Rx ¹⁾

pancreatic true cysts
pancreatic retention cysts
pancreatic mucinous non-neoplastic cysts
lymphoepithelial cysts (rare)
pancreatic pseudocysts (walled off pancreatic fluid collections)
pancreatic cystic neoplasms:
- intraductal papillary mucinous neoplasm of the pancreas
- serous cystic tumors
- mucinous cystic neoplasms
- solid pseudopapillary neoplasms

exocrine pancreatic adenocarcinoma
pancreatitis
islet cell tumour
lymphoma (rare)
- suggested by B symptoms, raised LDH, normal serum CA 19-9, size > 6cm, surrounding enlarged LNs
metastatic cancer (rare)

overall population lifetime risk 1.3%
non-hereditary chronic pancreatitis
- 26x relative risk over 7years
- cumulative risk: ~2% at 10 years, ~4% at 20 years
genetics:
- 5-10% have a 1st degree relative with exocrine pancreatic cancer
- esp. if age < 50yrs
- increased risk with:
  - familial pancreatic cancer
    - 2 or more 1st or 2nd degree family members ⇒ 18x relative risk
    - 3 or more family members ⇒ ~60x relative risk
  - hereditary breast cancer: BRCA and PALB2
  - p16, MLH1, MSH2, MSH6, or PMS2 mutations
  - Peutz-Jeghers syndrome
  - Familial atypical multiple-mole melanoma (FAMMM) syndrome
  - Ataxia-telangiectasia
  - Lynch syndrome and FAP
  - non-O blood groups:
    - blood gp A: 1.3x relative risk
    - blood gp AB: 1.5x relative risk
    - blood gp B: 1.7x relative risk
smoking
- at least 1.5x relative risk
type 2 diabetes mellitus
- perhaps a 2x relative risk
obesity, metabolic syndrome and lack of physical activity
- BMI > 30 appears to have a 1.7x relative risk
- metabolic syndrome (3 or more of TG > 1.7, HDL < 1.0 males or 1.3 females, fasting glucose > 6.1 and non-fasting > 7.8, BP > 130/85, BMI > 25) appears to increase risk ²⁾
height
- appears to have an increased relative risk of 1.8x
diet, alcohol, caffeine - controversial, no clear significant risk evident on present data

most patients present with:
- anorexia, weight loss
- epigastric pain
  - usually insidious onset with gnawing quality and may radiate to sides or back
  - often occurs even in small tumours
  - often helped by curling up into fetal position
  - rarely may present with pancreatitis if tumour obstructs pancreatic duct
half also present with:
- nausea
- back pain (especially with tumours arising in body or tail of pancreas)
some may present with progressive cholestatic jaundice (esp. if arises in pancreatic head, or late if due to liver mets), diarrhoea or vomiting
rarely may present with:
- new onset atypical diabetes mellitus
- thrombophlebitis
- nonbacterial thrombotic endocarditis and arterial emboli
- pancreatic panniculitis, especially involving the legs, particularly in patients with the acinar cell variant of pancreatic cancer
- cicatricial or bullous pemphigoid
may be discovered incidentally on CT scan (up to 7% of cases)
advanced disease is suggested by:
- abdominal mass
- ascites
- Virchow's node (left supraclavicular lymphadenopathy)
- Sister Mary Joseph's node periumbilical mass

only 1 in 8 survive more than 5 years from Dx
this is in part due to the thick, nearly impenetrable wall of fibrosis, or scar tissue, that surrounds most pancreatic tumors and makes it hard for drugs to access and destroy the cancer cells
- in 2023, a class of anti-cancer drugs called HDAC inhibitors may help treat pancreatic cancer by modulating the activation of fibroblasts - HDAC inhibitors both turned down the growth signals from the fibroblasts to the cancer cells and it reduced the actual activation and accumulation of the fibroblasts.³⁾

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