A Case of Pancreatic Ductal Adenocarcinoma Arising From Atypical Flat Lesions.

To the Editor:

Atypical flat lesions (AFLs) in the pancreas have been suggested a potential precursor to pancreatic ductal adenocarcinoma via acinar-to-ductal metaplasia (ADM) in mouse model studies. Still, the role of AFLs in human pancreatic cancer is unknown. Here, we present a case of KRAS-mutated pancreatic ductal adenocarcinoma arising from AFLs based on clear histopathological findings. This incidental finding highlights the need for further investigation of the prevalence and role of AFLs in human pancreatic ductal adenocarcinoma (PDAC) development.

CASE REPORT

A woman around 70 years old presented with abdominal pain and jaundice. No solid tumor was found on radiology, but suspicion of a malignant lesion was raised because of the presence of double duct sign,[1] and the patient subsequently underwent pancreaticoduodenectomy. Perioperatively, the pancreas was soft in texture and absent of macroscopic tumor signs.

Histopathological evaluation revealed KRAS-mutated PDAC with both a ductal growth pattern and a low differentiated growth pattern. The nonneoplastic pancreas was marked by chronic atrophic pancreatitis with extensive ADM positive for the ductal marker cytokeratin 7 (Fig. 1A). The metaplastic ductal epithelium consisted of inconspicuous cuboidal cells with centrally placed homogenous nuclei and a low proliferative activity indicated by less than 10% of Ki-67–positive nuclei (Fig. 1A). Only in 1 single acinus with ADM, pancreatic intraepithelial neoplasia (PanIN) grade I was observed.

FIGURE 1

A, Acinar-to-ductal metaplasia and atypical flat lesions (AFLs) stained with hematoxylin and eosin, the ductal marker cytokeratin 7 (CK7), and the proliferation marker Ki-67. Acinar-to-ductal metaplasia exhibits small CK7-positive glands without dysplasia and with a low Ki-67 proliferation rate. The AFL displays irregular CK7-positive gland formations with highly pleomorphic epithelial cells and a high Ki-67 proliferation rate. Original magnification ×200. B, Overview over an acinus with AFL (right) and a magnification showing the transition into invasive growth into the surrounding stroma (left). Original magnifications ×50 and ×400. Scale bars, 200 μm. C, Theoretical progression from normal exocrine pancreas parenchyma into invasive ductal adenocarcinoma. Original magnifications ×50 (top panel) and ×400 (bottom panel). Scale bars, 200 μm.

Several acini with metaplastic ductuli displayed dysplastic changes of the epithelium with pleomorphic hyperchromatic nuclei and a high proliferative activity with more than 50% of Ki-67–positive nuclei indicative of AFLs (Fig. 1A). In addition, some ducts showed back-to-back formations and shift toward a cribriform growth pattern. In 1 acinus with AFL, an outgrowth of a dysplastic gland into the surrounding connective tissue was detected as a clear sign of transition from AFL into infiltrative cancer growth (Fig. 1B).

DISCUSSION

Here, we present a case of PDAC that presents with extensive parenchymal atrophy and ADM as well as AFLs clearly progressing into infiltrating cancer. This case report shows that AFLs can progress to PDAC in human and probably via a sequence from chronic pancreatitis toward acinar atrophy and ADM (Fig. 1C).

Acinar-to-ductal metaplasia is defined as the metaplastic transformation of pancreatic acinar cells into small intra-acinar ductal CK7-positive cells. It can be induced by stress and inflammation including pancreatitis, KRAS mutation, and epidermal growth factor receptor activation.[2] In mice with KRAS mutation, ADM formation is an early event in PDAC progression.[3] In humans, ADM is commonly found close to PanIN lesions, but its role in PDAC progression is not clear. Shi et al[4] showed that ADM near PanIN lesions often shares the same KRAS mutation, whereas isolated ADM without adjacent PanIN foci is of wild-type KRAS. The authors argue against acinar cells being the cell of origin in PDAC but that ADM with KRAS mutations is more likely a retrograde expansion of PanIN lesions. An alternate interpretation is that ADMs that acquire a KRAS mutation develop into PanIN lesions.[2] The latter has been experimentally supported in mouse models.[5,6] We find it unlikely that the present PDAC case arose from PanIN lesions as only 1 low-grade PanIN was observed in an ADM area.

Alternatively, human PDAC might arise from ADM via AFLs, which has been recently shown in mouse models.[7,8] The presence of AFLs has also been demonstrated in human pancreas tissue, but without evidence of AFLs progressing into invasive carcinoma. Aichler et al[8] reported the presence of AFLs in 3 familial pancreatic cancer cases but could not find AFLs in any sporadic PDAC case. On the contrary, Morita et al[9] reviewed slides from 371 pancreatic specimens with different sporadic PDAC forms or benign lesions and identified AFLs in 18 cases. However, these findings do not clarify whether AFL is a precursor or only a bystander. In this case report, there is a clear progression from AFL into invasive carcinoma, which strongly suggests that AFL is the precursor lesion.

In summary, this case report shows for the first time in humans that PDAC can arise from AFLs. The prevalence of AFLs and its pathophysiological role in pancreatic cancer need further investigation.