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Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes.

Methods

Surgically resected IPMNs (n = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS, BRAF, and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined.

Results

There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type (p < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p < 0.05%).

Conclusions

There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.

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Abbreviations

BMP:

Bone morphogenetic protein

EGFR:

Epidermal growth factor receptor

ERK:

Extracellular signal-regulated kinase

IPMN:

Intraductal papillary mucinous neoplasm

IPMC:

Intraductal papillary mucinous carcinoma

PanIN:

Pancreatic intraepithelial neoplasia

PDAC:

Pancreatic ductal adenocarcinoma

PCR:

Polymerase chain reaction

MPD:

Main pancreatic duct

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Acknowledgments

We thank Drs. Norihiro Kokudo and Taku Aoki (Hepato-Biliary-Pancreatic Surgery Division, University of Tokyo) for the surgical sample acquisition. We also thank Mitsuko Tsubouchi and Sanae Ogawa for technical assistance. This study was supported by KAKENHI, grants of the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT) to M.O., K.K., and H.I.

Conflict of interest

The authors have no competing interests to disclose.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Dai Mohri, Yoshinari Asaoka, Hideaki Ijichi, Koji Miyabayashi, Yotaro Kudo, Yasuo Tanaka, Keisuke Tateishi, Hiroyuki Isayama, Minoru Tada, Masao Omata & Kazuhiko Koike

  2. Department of Gastroenterology, Kanto Central Hospital, 6-25-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8531, Japan

    Motoko Seto

  3. Department of Gastroenterology, Sanno Hospital, 8-10-16 Akasaka, Minato-ku, Tokyo, 107-0052, Japan

    Miki Ohta

  4. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan

    Motohisa Tada & Fumihiko Kanai

  5. Division of Clinical Genome Research, Institute of Medical Sciences, University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo, 108-8639, Japan

    Tsuneo Ikenoue

  6. Department of Diagnostic Pathology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Noriyoshi Fukushima

  7. Kawabe Clinic, 2-2-1 Midoricho, Koganei, Tokyo, 184-0003, Japan

    Takao Kawabe

  8. Yamanashi Prefectural Hospital Organization, 1-1-1 Fujimi, Kofu, Yamanashi, 400-8506, Japan

    Masao Omata

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  1. Dai Mohri
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Correspondence to Hideaki Ijichi.

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Mohri, D., Asaoka, Y., Ijichi, H. et al. Different subtypes of intraductal papillary mucinous neoplasm in the pancreas have distinct pathways to pancreatic cancer progression. J Gastroenterol 47, 203–213 (2012). https://doi.org/10.1007/s00535-011-0482-y

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  • DOI: https://doi.org/10.1007/s00535-011-0482-y

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