Histo-molecular oncogenesis of pancreatic cancer: From precancerous lesions to invasive ductal adenocarcinoma

Table 1 Immunohistochemical markers for intraductal papillary mucinous neoplasm/intraductal tubulo-papillary neoplasm histopathological classification

Type of lesion	Subtype	MUC1	MUC2	MUC5AC	MUC6	CDX2
IPMN	G	Negative	Negative	Positive1	Negative	Negative
	PB	Positive1	Negative	Positive1	Positive	Negative
	INT	Negative	Positive1	Positive1	Negative	Positive1
	ONC	Positive	Negative	Positive	Positive1	Negative
ITPN		Positive	Negative	Negative	Positive1	Negative

IPMN: Intraductal papillary mucinous neoplasm; ITPN: Intraductal tubulo-papillary neoplasm; G: Gastric; PB: Pancreaticobiliary; INT: Intestinal; ONC: Oncocytic.

¹The positivity of a marker is very intense at the immunohistochemical level (++).

Table 2 Precursor lesions and their most important histopathological and molecular features

Precursor lesions	Main histopathological features	Molecular hallmarks
PanIN	Non-infiltrating lesions involving pancreatic ducts and < 0.5 cm, composed of cuboid to columnar mucinous cells, with two degrees of dysplasia: (1) Low-grade PanINs include the previously called PanIN-1 and PanIN-2; and (2) high-grade PanINs include PanIN-3	KRAS somatic mutations are early molecular events (Low-grade PanINs); CDKN2A, TP53, and SMAD4 mutations are late molecular events (High-grade PanINs)
IPMN	Non-infiltrating intraductal neoplasms > 1.0 cm composed of mucinous cells with papillary architecture. IPMNs have two degrees of dysplasia: (1) Low-grade IPMNs; and (2) High-grade IPMNs. IPMNs can be classified based on topography (main duct, branch duct or mixed) and also on histology (gastric, pancreaticobiliary, intestinal, or oncocytic type, see Table 1)	GNAS and KRAS are altered in up to 60% and to 80% of IPMNs, respectively There are two possible carcinogenetic processes: (1) GNAS mutations cause progression to colloid carcinomas; and (2) KRAS mutations lead to conventional PDAC. Other frequently mutated genes in IPMNs are RNF43, BRAF, TP53, and SMAD4
MCN	Composed of columnar cells with abundant mucin located in the upper part. There are two degrees of dysplasia: (1) Low-grade MCN; and (2) High-grade MCN. The histopathologic clues for MCN diagnosis are the lack of communication with the pancreatic ductal tree and the presence of an ovarian-like stroma under the mucinous epithelium	There are fewer mutations and chromosomal alterations in MCNs compared with other precursors, and this could explain the lower frequency of progression of MCN to PDAC. Frequently altered genes are KRAS, CDKN2A, TP53, SMAD4, and RNF43
ITPN	Composed of uniform cuboidal cells without a significant amount of mucin, arranged in densely packed tubules and back-to-back glands with a typical intraductal, tubulopapillary growth	PIK3CA mutations and AKT alterations are frequently seen in ITPNs. Mutations involving KRAS, NRAS, and GNAS are very rare in ITPNs

PanIN: Pancreatic intraepithelial neoplasm; IPMN: Intraductal papillary mucinous neoplasm; MCN: Mucinous cystic neoplasm; ITPN: Intratubular papillary neoplasm; PDAC: Pancreatic ductal adenocarcinoma.