Virchows Archiv

, Volume 472, Issue 3, pp 383–393 | Cite as

Distinct histopathological characteristics in colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp and conventional tubular adenoma

  • Takashi Murakami
  • Hiroyuki Mitomi
  • Takashi Yao
  • Tsuyoshi Saito
  • Tomoyoshi Shibuya
  • Naoto Sakamoto
  • Taro Osada
  • Sumio Watanabe
Original Article


The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts.


Sessile serrated adenoma/polyp Submucosal invasive carcinoma Serrated neoplasia pathway Conventional adenoma-carcinoma sequence Histopathology 



The authors thank Mrs. Keiko Mitani for her assistance with histology. The work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (#24590429 to H. Mitomi and #15K19059 to T. Murakami).


This work was supported in part by a Grant-in-Aid from the Japan Society for the Promotion of Science (#24590429 to H. Mitomi and #15K19059 to T. Murakami).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the Institutional Review Board and the ethical committee of our hospital (registration #2012015). For this retrospective study, no informed consent was required.


  1. 1.
    Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM (2003) Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27:65–81CrossRefPubMedGoogle Scholar
  2. 2.
    Kambara T, Simms LA, Whitehall VL et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53:1137–1144CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    O'Brien MJ, Yang S, Mack C et al (2006) Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 30:1491–1501CrossRefPubMedGoogle Scholar
  4. 4.
    Patil DT, Shadrach BL, Rybicki LA, Leach BH, Pai RK (2012) Proximal colon cancers and the serrated pathway: a systematic analysis of precursor histology and BRAF mutation status. Mod Pathol 25:1423–1431CrossRefPubMedGoogle Scholar
  5. 5.
    Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767CrossRefPubMedGoogle Scholar
  6. 6.
    Jass JR, Baker K, Zlobec I et al (2006) Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer. Histopathology 49:121–131CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Spring KJ, Zhao ZZ, Karamatic R et al (2006) High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 131:1400–1407CrossRefPubMedGoogle Scholar
  8. 8.
    Kim YH, Kakar S, Cun L, Deng G, Kim YS (2008) Distinct CpG island methylation profiles and BRAF mutation status in serrated and adenomatous colorectal polyps. Int J Cancer 123:2587–2593CrossRefPubMedGoogle Scholar
  9. 9.
    Sandmeier D, Benhattar J, Martin P, Bouzourene H (2009) Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps. Histopathology 55:206–213CrossRefPubMedGoogle Scholar
  10. 10.
    Carr NJ, Mahajan H, Tan KL, Hawkins NJ, Ward RL (2009) Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma. J Clin Pathol 62:516–518CrossRefPubMedGoogle Scholar
  11. 11.
    Yachida S, Mudali S, Martin SA, Montgomery EA, Iacobuzio-Donahue CA (2009) Beta-catenin nuclear labeling is a common feature of sessile serrated adenomas and correlates with early neoplastic progression after BRAF activation. Am J Surg Pathol 33:1823–1832CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kim KM, Lee EJ, Ha S et al (2011) Molecular features of colorectal hyperplastic polyps and sessile serrated adenoma/polyps from Korea. Am J Surg Pathol 35:1274–1286CrossRefPubMedGoogle Scholar
  13. 13.
    Dhir M, Yachida S, Van Neste L et al (2011) Sessile serrated adenomas and classical adenomas: an epigenetic perspective on premalignant neoplastic lesions of the gastrointestinal tract. Int J Cancer 129:1889–1898CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fujita K, Yamamoto H, Matsumoto T et al (2011) Sessile serrated adenoma with early neoplastic progression: a clinicopathologic and molecular study. Am J Surg Pathol 35:295–304CrossRefPubMedGoogle Scholar
  15. 15.
    Alexander J, Watanabe T, Wu TT, Rashid A, Li S, Hamilton SR (2001) Histopathological identification of colon cancer with microsatellite instability. Am J Pathol 158:527–535CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sheridan TB, Fenton H, Lewin MR et al (2006) Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions “caught in the act.”. Am J Clin Pathol 126:564–571CrossRefPubMedGoogle Scholar
  17. 17.
    Lash RH, Genta RM, Schuler CM (2010) Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol 63:681–686CrossRefPubMedGoogle Scholar
  18. 18.
    Wada R, Morimoto T, Inayoshi T (2014) Pathological features of the sessile serrated adenoma/polyp with special references of its carcinogenesis. Med Mol Morphol 47:123–129CrossRefPubMedGoogle Scholar
  19. 19.
    Ban S, Mitomi H, Horiguchi H, Sato H, Shimizu M (2014) Adenocarcinoma arising in small sessile serrated adenoma/polyp (SSA/P) of the colon: clinicopathological study of eight lesions. Pathol Int 64:123–132CrossRefPubMedGoogle Scholar
  20. 20.
    Chino A, Yamamoto N, Kato Y et al (2016) The frequency of early colorectal cancer derived from sessile serrated adenoma/polyps among 1858 serrated polyps from a single institution. Int J Color Dis 31:343–349CrossRefGoogle Scholar
  21. 21.
    Bettington M, Walker N, Rosty C et al (2017) Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut 66:97–106CrossRefPubMedGoogle Scholar
  22. 22.
    Murakami T, Mitomi H, Saito T et al (2015) Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum. Mod Pathol 28:146–158CrossRefPubMedGoogle Scholar
  23. 23.
    Watanabe T, Itabashi M, Shimada Y et al (2012) Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol 17:1–29CrossRefPubMedGoogle Scholar
  24. 24.
    Roxburgh CS, McMillan DC, Richards CH et al (2014) The clinical utility of the combination of T stage and venous invasion to predict survival in patients undergoing surgery for colorectal cancer. Ann Surg 259:1156–1165CrossRefPubMedGoogle Scholar
  25. 25.
    Goldstein NS (2006) Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases. Am J Clin Pathol 125:132–145CrossRefPubMedGoogle Scholar
  26. 26.
    García-Solano J, Conesa-Zamora P, Trujillo-Santos J, Mäkinen MJ, Pérez-Guillermo M (2011) Tumour budding and other prognostic pathological features at invasive margins in serrated colorectal adenocarcinoma: a comparative study with conventional carcinoma. Histopathology 59:1046–1056CrossRefPubMedGoogle Scholar
  27. 27.
    Loy TS, Kaplan PA (2004) Villous adenocarcinoma of the colon and rectum: a clinicopathologic study of 36 cases. Am J Surg Pathol 28:1460–1465CrossRefPubMedGoogle Scholar
  28. 28.
    Kawachi H, Eishi Y, Ueno H et al (2015) A three-tier classification system based on the depth of submucosal invasion and budding/sprouting can improve the treatment strategy for T1 colorectal cancer: a retrospective multicenter study. Mod Pathol 28:872–879CrossRefPubMedGoogle Scholar
  29. 29.
    Jenkins MA, Hayashi S, O'Shea AM et al (2007) Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 133:48–56CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ueno H, Hashiguchi Y, Shimazaki H et al (2013) Objective criteria for crohn-like lymphoid reaction in colorectal cancer. Am J Clin Pathol 139:434–441CrossRefPubMedGoogle Scholar
  31. 31.
    Kimura R, Fujimori T, Ichikawa K et al (2012) Desmoplastic reaction in biopsy specimens of early colorectal cancer: a Japanese prospective multicenter study. Pathol Int 62:525–531CrossRefPubMedGoogle Scholar
  32. 32.
    Burgess NG, Pellise M, Nanda KS et al (2016) Clinical and endoscopic predictors of cytological dysplasia or cancer in a prospective multicentre study of large sessile serrated adenomas/polyps. Gut 65:437–446CrossRefPubMedGoogle Scholar
  33. 33.
    Bouwens MW, van Herwaarden YJ, Winkens B et al (2014) Endoscopic characterization of sessile serrated adenomas/polyps with and without dysplasia. Endoscopy 46:225–235CrossRefPubMedGoogle Scholar
  34. 34.
    Murakami T, Sakamoto N, Ritsuno H et al (2017) Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. Gastrointest Endosc 85:590–600CrossRefPubMedGoogle Scholar
  35. 35.
    Saitoh Y, Waxman I, West AB et al (2001) Prevalence and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology 120:1657–1665CrossRefPubMedGoogle Scholar
  36. 36.
    Aldridge AJ, Simson JN (2001) Histological assessment of colorectal adenomas by size. Are polyps less than 10 mm in size clinically important? Eur J Surg 167:777–781CrossRefPubMedGoogle Scholar
  37. 37.
    Tanaka S, Haruma K, Teixeira CR et al (1995) Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis. J Gastroenterol 30:710–717CrossRefPubMedGoogle Scholar
  38. 38.
    Kobayashi H, Mochizuki H, Morita T et al (2011) Characteristics of recurrence after curative resection for T1 colorectal cancer: Japanese multicenter study. J Gastroenterol 46:203–211CrossRefPubMedGoogle Scholar
  39. 39.
    Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM (2005) Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol 18:170–178CrossRefPubMedGoogle Scholar
  40. 40.
    Tuppurainen K, Mäkinen JM, Junttila O et al (2005) Morphology and microsatellite instability in sporadic serrated and non-serrated colorectal cancer. J Pathol 207:285–294CrossRefPubMedGoogle Scholar
  41. 41.
    Gafà R, Maestri I, Matteuzzi M et al (2000) Sporadic colorectal adenocarcinomas with high-frequency microsatellite instability. Cancer 89:2025–2037CrossRefPubMedGoogle Scholar
  42. 42.
    Greenson JK, Huang SC, Herron C et al (2009) Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol 33:126–133CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hyde A, Fontaine D, Stuckless S et al (2010) A histology-based model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol 34:1820–1829CrossRefPubMedGoogle Scholar
  44. 44.
    Wright CL, Stewart ID (2003) Histopathology and mismatch repair status of 458 consecutive colorectal carcinomas. J Surg Pathol 27:1393–1406CrossRefGoogle Scholar
  45. 45.
    Sis B, Sarioglu S, Sokmen S, Sakar M, Kupelioglu A, Fuzun M (2005) Desmoplasia measured by computer assisted image analysis: an independent prognostic marker in colorectal carcinoma. J Clin Pathol 58:32–38CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stefanius K, Ylitalo L, Tuomisto A et al (2011) Frequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma. Histopathology 58:679–692CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Tamaru Y, Oka S, Tanaka S et al (2017) Long-term outcomes after treatment for T1 colorectal carcinoma: a multicenter retrospective cohort study of Hiroshima GI Endoscopy Research Group. J Gastroenterol.
  48. 48.
    Pai RK, Jayachandran P, Koong AC et al (2012) BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. Am J Surg Pathol 36:744–752CrossRefPubMedGoogle Scholar
  49. 49.
    Samowitz WS, Sweeney C, Herrick J et al (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65:6063–6069CrossRefPubMedGoogle Scholar
  50. 50.
    Pritchard CC, Grady WM (2011) Colorectal cancer molecular biology moves into clinical practice. Gut 60:116–129CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland 2017

Authors and Affiliations

  1. 1.Department of GastroenterologyJuntendo University School of MedicineTokyoJapan
  2. 2.Department of Human PathologyJuntendo University School of MedicineTokyoJapan
  3. 3.Department of Diagnostic Pathology and Laboratory MedicineOdawara Municipal HospitalOdawaraJapan

Personalised recommendations