Gastric Cancer

, Volume 20, Issue 6, pp 929–939 | Cite as

Long-term follow-up study of gastric adenoma; tumor-associated macrophages are associated to carcinoma development in gastric adenoma

  • Daiki Taniyama
  • Kiyomi Taniyama
  • Kazuya Kuraoka
  • Junichi Zaitsu
  • Akihisa Saito
  • Hirofumi Nakatsuka
  • Naoya Sakamoto
  • Kazuhiro Sentani
  • Naohide Oue
  • Wataru Yasui
Original Article



Some gastric adenomas may progress to adenocarcinoma in a short time, but others remain as adenoma for a long time.


Among 1138 cases diagnosed as adenoma by biopsy at Kure Medical Association Hospital between 1990 and 2010, 51 adenomas were enrolled. Of these, 28 adenomas (group A) were followed for 60 months or longer with no progression to adenocarcinoma within 60 months, and the other 23 adenomas (group B) were upgraded to carcinoma by consecutive biopsies performed within 1 year after the first biopsy. These adenomas were compared clinicopathologically and immunohistochemically.


Macroscopically, the mean size of group B adenomas was significantly larger than that of group A adenomas (18.6 vs. 9.9 mm) at the first biopsy. The frequency of a depressed area in the adenoma was significantly higher in group B than group A. Microscopically none of group A but 7 (30.4%) of 23 group B adenomas showed severe atypia. Each of a highly proliferative gland measured by Ki-67 labeling, cellular atypical grade, gastric phenotype defined by MUC5AC and MUC6 and CD204-positive tumor-associated macrophage (TAM) was a significant risk factor for adenocarcinoma development in gastric adenoma by univariate analysis. Only moderate or severe atypia of adenoma cells and the TAM number in the stroma of adenomas were independent risk factors by multivariate analysis.


As independent risk factors, cellular atypia may reconfirm the importance of morphological analysis, and the TAM number may indicate the significance of TAM function in gastric adenoma.


Gastric adenoma Adenoma-carcinoma sequence Tumor-associated macrophages 



The authors would like to thank Mitsuki Nishimura, Akiko Ishimoto, Mayumi Takeuchi and Yoko Kodama for their excellent technical assistance and organization of this research. This work was supported financially in part by the National Hospital Organization of Japan.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

Human rights statement and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients for being included in the study.

Supplementary material

10120_2017_713_MOESM1_ESM.pdf (61 kb)
Supplementary Figure 1. Clinicopathological course of group A. U: upper; M: middle; L: lower parts; Y, Yamada; EMR: endoscopic mucosal resection; Well: well differentiated; Mod: moderately differentiated; Por: poorly differentiated; Pap; papillary adenocarcinoma (PDF 60 kb)
10120_2017_713_MOESM2_ESM.pdf (51 kb)
Supplementary Figure 2. Clinicopathological course of group B. U: upper; M: middle; L: lower parts; Y, Yamada; EMR: endoscopic mucosal resection; OPE, operation; Well: well differentiated; Mod: moderately differentiated; Por: poorly differentiated; Pap; papillary adenocarcinoma (PDF 50 kb)


  1. 1.
    Goldstein NS, Lewin KJ. Gastric epithelial dysplasia and adenoma: historical review and histological criteria for grading. Hum Pathol. 1997;28:127–33.CrossRefPubMedGoogle Scholar
  2. 2.
    Park do Y, Lauwers GY. Gastric polyps: classification and management. Arch Pathol Lab Med. 2008;132:633–40.PubMedGoogle Scholar
  3. 3.
    Stolte M, Sticht T, Eidt S, Ebert D, Finkenzeller G. Frequency, location, and age and sex distribution of various types of gastric polyp. Endoscopy. 1994;26:659–65.CrossRefPubMedGoogle Scholar
  4. 4.
    Nakamura T, Nakano G. Histopathological classification and malignant change in gastric polyps. J Clin Pathol. 1985;38:754–64.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hattori T. Morphological range of hyperplastic polyps and carcinomas arising in hyperplastic polyps of the stomach. J Clin Pathol. 1985;38:622–30.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Goddard AF, Badreldin R, Pritchard DM, Walker MM, Warren B. The management of gastric polyps. Gut. 2010;59:1270–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Tsukashita S, Kushima R, Bamba M, Sugihara H, Hattori T. MUC gene expression and histogenesis of adenocarcinoma of the stomach. Int J Cancer. 2001;94:166–70.CrossRefPubMedGoogle Scholar
  8. 8.
    Miwa K, Doyama H, Hirano K, Inagaki S, Waseda Y, Goto Y, et al. Is endoscopic differential diagnosis possible between adenoma and adenocarcinoma in the cases with biopsy—based preoperative diagnosis of gastric adenoma treated by endoscopic submucosal dissection? Endosc Forum Dig Dis. 2010;26:17–26.Google Scholar
  9. 9.
    Lauwers GY, Riddell RH. Gastric epithelial dysplasia. Gut. 1999;45:784–90.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lansdown M, Quirke P, Dixon MF, Axon AT, Johnston D. High grade dysplasia of the gastric mucosa: a marker for gastric carcinoma. Gut. 1990;31:977–83.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kolodziejczyk P, Yao T, Oya M, Nakamura S, Utsunomiya T, Ishikawa T, et al. Long-term follow-up study of patients with gastric adenomas with malignant transformation. An immunohistochemical and histochemical analysis. Cancer. 1994;74:2896–907.CrossRefPubMedGoogle Scholar
  12. 12.
    Yamada H, Ikegami M, Shimoda T, Takagi N, Maruyama M. Long-term follow-up study of gastric adenoma/dysplasia. Endoscopy. 2004;36:390–6.CrossRefPubMedGoogle Scholar
  13. 13.
    Sung JK. Diagnosis and management of gastric dysplasia. Korean J Intern Med. 2016;31:201–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Di Gregorio C, Morandi P, Fante R, De Gaetani C. Gastric dysplasia. A follow-up study. Am J Gastroenterol. 1993;88:1714–9.PubMedGoogle Scholar
  15. 15.
    Rugge M, Farinati F, Baffa R, Sonego F, Di Mario F, Leandro G, et al. Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology. 1994;107:1288–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Saraga EP, Gardiol D, Costa J. Gastric dysplasia. A histological follow-up study. Am J Surg Pathol. 1987;11:788–96.CrossRefPubMedGoogle Scholar
  17. 17.
    Fertitta AM, Comin U, Terruzzi V, Minoli G, Zambelli A, Cannatelli G, et al. Clinical significance of gastric dysplasia: a multicenter follow-up study. Gastrointestinal Endoscopic Pathology Study Group. Endoscopy. 1993;25:265–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Kokkola A, Haapiainen R, Laxen F, Puolakkainen P, Kivilaakso E, Virtamo J, et al. Risk of gastric carcinoma in patients with mucosal dysplasia associated with atrophic gastritis: a follow up study. J Clin Pathol. 1996;49:979–84.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8:755–68.CrossRefPubMedGoogle Scholar
  20. 20.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.CrossRefPubMedGoogle Scholar
  21. 21.
    Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Euro J Cancer (Oxford, England: 1990). 2006;42:717–27.CrossRefGoogle Scholar
  22. 22.
    Tsutsui S, Yasuda K, Suzuki K, Tahara K, Higashi H, Era S. Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep. 2005;14:425–31.PubMedGoogle Scholar
  23. 23.
    Ohtaki Y, Ishii G, Nagai K, Ashimine S, Kuwata T, Hishida T, et al. Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2010;5:1507–15.Google Scholar
  24. 24.
    Lissbrant IF, Stattin P, Wikstrom P, Damber JE, Egevad L, Bergh A. Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol. 2000;17:445–51.PubMedGoogle Scholar
  25. 25.
    Yoshikawa K, Mitsunaga S, Kinoshita T, Konishi M, Takahashi S, Gotohda N, et al. Impact of tumor-associated macrophages on invasive ductal carcinoma of the pancreas head. Cancer Sci. 2012;103:2012–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Sano T, Aiko T. New Japanese classifications and treatment guidelines for gastric cancer: revision concepts and major revised points. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2011;14:97–100.Google Scholar
  27. 27.
    Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000;47:251–5.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Taniyama K, Ishida K, Toda T, Motoshita J, Kuraoka K, Saito A, et al. Tyrosine1248-phosphorylated HER2 expression and HER2 gene amplification in female invasive ductal carcinomas. Breast cancer (Tokyo, Japan). 2008;15:231–40.CrossRefGoogle Scholar
  29. 29.
    Oue N, Sentani K, Noguchi T, Ohara S, Sakamoto N, Hayashi T, et al. Serum olfactomedin 4 (GW112, hGC-1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer patients. Int J Cancer. 2009;125:2383–92.CrossRefPubMedGoogle Scholar
  30. 30.
    Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi T, et al. Systematic search for gastric cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel prognostic factors in patients with gastric cancer. Oncogene. 2006;25:2546–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Nagatomi Y, Kawamura S, Kawashima M, Harima K, Maetani N, Azuma M, et al. Clinical follow-up of protruded atypical epithelial foci of the stomach. Gastroenterol Endosc. 1980;22:275-83_1.Google Scholar
  32. 32.
    Katakura T, Masuda T, Ikeda T, Abe S, Shimada T, Shibuki S, et al. Immunohistochemical studies in depressed type adenomas of the stomach–comparison with protruded type adenomas and depressed type well differentiated mucosal gastric cancers. Nihon Shokakibyo Gakkai zasshi=. Jpn J Gastro-Enterol. 1998;95:992–1000.Google Scholar
  33. 33.
    Mori G, Oda I, Taniguchi H, Miyamoto Y, Sekiguchi M, Abe S, et al. Endoscopic surveillance for clinical management of gastric adenoma. Stomach Intestine. 2014;49:1859–69.Google Scholar
  34. 34.
    Jang B-G, Kim WH. Molecular pathology of gastric carcinoma. Pathobiology. 2011;78:302–10.CrossRefPubMedGoogle Scholar
  35. 35.
    Fenoglio-Preiser C, Wang J, Stemmermann G, Noffsinger A. TP53 and gastric carcinoma: a review. Hum Mutat. 2003;21:258–70.CrossRefPubMedGoogle Scholar
  36. 36.
    Nishimura R, Mukaisho K, Yamamoto H, Sonoda A, Andoh A, Fujiyama Y, et al. Precursor-derived versus de-novo carcinogenesis depends on lineage-specific mucin phenotypes of intramucosal gland-forming gastric neoplasms. Histopathology. 2013;63:616–29.PubMedGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2017

Authors and Affiliations

  • Daiki Taniyama
    • 1
    • 2
    • 3
  • Kiyomi Taniyama
    • 1
    • 2
    • 3
  • Kazuya Kuraoka
    • 2
    • 3
  • Junichi Zaitsu
    • 2
    • 3
  • Akihisa Saito
    • 2
    • 3
  • Hirofumi Nakatsuka
    • 4
  • Naoya Sakamoto
    • 1
  • Kazuhiro Sentani
    • 1
  • Naohide Oue
    • 1
  • Wataru Yasui
    • 1
  1. 1.Department of Molecular PathologyHiroshima University Institute of Biomedical and Health SciencesHiroshimaJapan
  2. 2.Institute for Clinical ResearchNational Hospital Organization, Kure Medical Center and Chugoku Cancer CenterKureJapan
  3. 3.Department of Diagnostic PathologyNational Hospital Organization, Kure Medical Center and Chugoku Cancer CenterKureJapan
  4. 4.Department of SurgeryKure Medical Association HospitalKureJapan

Personalised recommendations