Pancreatic adenocarcinoma pathology: changing "landscape"

Abstract

Pancreatic cancer is a devastating disease. At time of diagnosis the disease is usually advanced and only a minority of patients are eligible for surgical resection. The overall 5-year survival is 6%. However, survival of patients with early stage pancreatic cancer is significantly better. To improve the prognosis of patients with pancreatic cancer, it is essential to diagnose and treat pancreatic cancer in the earliest stage. Prevention of pancreatic cancer by treating noninvasive precursor lesions just before they invade tissues can potentially lead to even better outcomes. Pancreatic carcinogenesis results from a stepwise progression in which accumulating genetic alterations drive neoplastic progression in well-defined precursor lesions, ultimately giving rise to an invasive adenocarcinoma. A thorough understanding of the genetic changes that drive pancreatic carcinogenesis can lead to identification of biomarkers for early detection and targets for therapy. Recent next-generation sequencing (NGS) studies have shed new light on our understanding of the natural history of pancreatic cancer and the precursor lesions that give rise to these cancers. Importantly, there is a significant window of opportunity for early detection and treatment between the first genetic alteration in a cell in the pancreas and development of full-blown pancreatic cancer. The current views on the pathology and genetics of pancreatic carcinogenesis that evolved from studies of pancreatic cancer and its precursor lesions are discussed in this review.

Keywords: Pancreatic cancer; genetics; intraductal papillary mucinous neoplasm (IPMN); pancreatic intraepithelial neoplasia (PanIN); precursor lesions.

Figure 1

PanIN progression model of pancreatic cancer. Each step in the progression from normal epithelium to low-grade PanIN, and on to high-grade PanIN is accompanied by accumulating genetic alterations. From left to right: a normal pancreatic duct is lined by cuboidal to low-columnar epithelium with amphophilic cytoplasm. PanIN-1A shows flat epithelial lining with tall columnar cells with basally located nuclei and abundant supranuclear mucin. PanIN-1B identical to PanIN-1A except for a papillary, micropapillary, or basally pseudostratified architecture in PanIN-1B. PanIN-2 demonstrates full-thickness pseudostratification of nuclei with mild-to-moderate cytologic abnormalities. PanIN-3 is characterized by complete loss of polarity, budding of cellular tufts into the duct lumen, and significant nuclear pleomorphism. PanIN, pancreatic intraepithelial neoplasia.

Figure 2

Endoscopic picture of a bulging ampulla of Vater with extruding thick mucin in a patient with an IPMN, sometimes referred to as “fish-eye” ampulla, and virtually pathognomonic of IPMN. IPMN, intraductal papillary mucinous neoplasm.

Figure 3

(A) Gastric-foveolar type IPMN with areas with low-grade (arrow) and intermediate-grade dysplasia (arrowhead); (B) gastric-foveolar type IPMN with transition from intermediate-grade dysplasia (arrow) to high-grade dysplasia (arrowhead). IPMN, intraductal papillary mucinous neoplasm.

Figure 4

(A) Intestinal type IPMN with intermediate-grade dysplasia; (B) mucinous adenocarcinoma (arrow) arising from an intestinal type IPMN (arrowhead). IPMN, intraductal papillary mucinous neoplasm.

Figure 5

Pancreatobiliary type IPMN with high-grade dysplasia. IPMN, intraductal papillary mucinous neoplasm.

Figure 6

Oncocytic type IPMN with high-grade dysplasia. (A) Overview; (B) detail. IPMN, intraductal papillary mucinous neoplasm.

Figure 7

Intraductal tubulopapillary neoplasm with high-grade dysplasia. (A) Overview; (B) detail.

Figure 8

TP53 immunohistochemistry showing strong aberrant expression of TP53 consistent with somatic TP53 mutation in a pancreatic ductal adenocarcinoma. A somatic mutation of TP53 was confirmed in this case.

Figure 9

SMAD4 immunohistochemistry showing loss of SMAD4 expression in a pancreatic ductal adenocarcinoma. Note the normal expression in surrounding stromal cells compared to negativity in tumor cells.

Figure 10

(A) Mucinous cystic neoplasm with low- to intermediate-grade dysplasia and focal goblet cells (arrow). Note the cellular ovarian-type stroma (asterix); (B) mucinous cystic neoplasm with high-grade dysplasia and typical ovarian-type stroma (asterix).