Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer

Abstract

We screened 116 patients with a strong family history of pancreatic cancer using a combination of endoscopic ultrasound and computed tomography. Ten of these patients underwent surgical resection at our institution, providing an opportunity to define the morphology of pancreatic precursor lesions in patients with a strong family history of pancreatic cancer. Eight of the 10 pancreata were available and these were entirely submitted for histologic examination. The number of pancreatic intraepithelial neoplasia (PanIN) lesions and intraductal papillary mucinous neoplasms (IPMNs) were compared with age-matched controls. Parenchymal changes were defined. Selected precursor neoplasms from 6 pancreata were microdissected and analyzed for KRAS gene mutations. PanINs were significantly more common in the 8 cases (mean of 10.7% of the duct profiles, range 1.0% to 27.3%) than in the controls (mean 1.9%, range 0% to 9.2%, P<0.01). Different KRAS gene mutations were identified in separately microdissected precursor lesions in 2 of 6 cases. IPMNs were identified in 4 of the 8 cases, including 2 pancreata each having 2 distinct IPMNs. Both the IPMNs and the PanINs, even the low-grade PanIN-1 lesions, were associated with lobular parenchymal atrophy. Some individuals with a strong family history of pancreatic cancer develop multifocal, noninvasive epithelial precursor lesions of the pancreas. PanINs and IPMNs produce obstructive lobular atrophy, and this atrophy is likely the source of the chronic pancreatitis-like changes seen in these patients. The multifocal nature of familial pancreatic neoplasia suggests that surveillance of these patients is warranted after partial pancreatectomy.

FIGURE 1

Normal pancreatic lobule (A) and progressive lobular atrophy (B–F). The earliest changes included a mild dilatation of the acinar lumina associated with a thinning of the acinar cells and a subtle loss of acinar granularity (B). More significant lobular atrophy included a considerable loss of acinar cells such that only a few cells with granular eosinophilic cytoplasm remained (C–E). Eventually no acinar cells, and in some lobules no ductal cells, remained (F).

FIGURE 2

In most of the pancreata there was a dramatic association between PanIN and the lobular atrophy (A–D). For example, in (A) notice the normal lobules associated with a normal duct (top) contrasting with the dramatic atrophy of the 3 lobular units associated with PanIN lesions involving 3 branching ducts toward the center and lower half of the field. Similar associations between PanINs and lobular atrophy can be appreciated in (B–D).

FIGURE 3

Low-magnification image of a PanIN, in a patient without a family history, associated with lobular parenchymal atrophy (A). High-magnification view of a PanIN-1A lesion in a control associated with lobular atrophy (B). Note the few remaining acini associated with the duct, the fibrosis, and the aggregation of islets. Low-magnification and high-magnification views of a PanIN-1A lesion in a control associated with lobular atrophy (C and D).

FIGURE 4

Percentage of ducts with PanIN lesions versus the EUS score for the 8 cases included in this analysis.