Pancreatic cancer

Pancreatic cancer is a disease of older people, with a peak incidence in people aged 65-74 years.[8] The only consistently reported exogenous risk factor for pancreatic cancer is cigarette smoking.[12][13]

It is estimated that at least 5% of all patients with pancreatic cancer have an inherited component.[14] Inherited cancer syndromes associated with pancreatic cancer are hereditary pancreatitis, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, familial breast cancer syndrome, and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome).[15][16][17]

About 65% of tumours are located within the head of the pancreas, 15% are in the body, 10% are in the tail, and 10% are multifocal. Characteristically, there is a strong desmoplastic stroma, which can account for >60% of the tumour mass. Lymph node metastases are common (40% to 75% of tumours <2 cm), as well as perineural and vascular invasion. Distant metastases are usually found in liver, lung, skin, and brain.[18]

Molecular and histopathological analyses have identified three distinct precursor lesions: pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm, and mucinous cystic neoplasm.[2] PanINs are the most commonly occurring microscopic precursor lesions (<5 mm), defined as neoplastic epithelial proliferations in the small pancreatic ducts, and are classified as PanIN-1, PanIN-2, or PanIN-3, based on their degree of differentiation.[19] Of the cystic neoplasms, the most common are intraductal papillary mucinous neoplasms, which are macroscopic precursors arising from the main pancreatic duct or its branches.[19] While 85% to 90% of the cases originate from the PanINs, 10% to 15% originate from intraductal papillary mucinous neoplasms or mucinous cystic neoplasms.[19] The progression from normal epithelium to invasive carcinoma has been proposed to follow a linear progression model, associated with accumulation of genetic alterations. Early genetic alterations include telomere shortening and mutations in the KRAS2 oncogene (occurring in >90% of early PanIN lesions), followed by inactivation of the p16/CDKN2A tumour suppressor gene and late alterations including inactivation of the TP53 and SMAD4 tumour suppressor genes.[20] Activating mutations in the NTRK gene, which encodes neurotrophic tropomyosin-receptor kinase (TRK), affect <1% of patients with pancreatic adenocarcinoma; such patients may benefit from targeted treatment with TRK protein inhibitors.[21]

Histological classification of invasive ductal adenocarcinoma[3][4]

Histological features of invasive ductal adenocarcinoma include the following:

Tubular adenocarcinoma (most common form)
Adenosquamous carcinoma
Colloid (mucinous non-cystic) adenocarcinoma: almost always arises in association with intraductal papillary mucinous neoplasm and is characterised by well-differentiated neoplastic epithelial cells within large pools of mucin infiltrating stroma
Hepatoid carcinoma
Medullary carcinoma: characterised by poor differentiation with microsatellite instability, a syncytial growth pattern, and pushing borders
Signet ring cell carcinoma
Undifferentiated carcinoma: highly malignant epithelial neoplasms without a more definite direction of differentiation, typically non-cohesive, and characterised by loss of E-cadherin expression
Undifferentiated carcinoma with osteoclast-like giant cells: arises frequently in association with a non-invasive precursor neoplasm such as mucinous cystic neoplasm, and is characterised by a mixture of atypical pleomorphic cells and multinucleated giant cells with uniform nuclei.

Pathophysiology

Classification

Histological classification of invasive ductal adenocarcinoma[3][4]