Skip to main content
SpringerLink
Log in

Biomarkers in Gastrointestinal System Carcinomas

  • Chapter
  • First Online:
Biomarkers in Carcinoma of Unknown Primary

Abstract

Gastrointestinal cancers constitute about one fourth of all cancer cases worldwide with high mortality and morbidity rates. While carcinomas arising from the gastrointestinal tract are usually adenocarcinomas, other types of neoplasms such as squamous cell carcinoma or neuroendocrine carcinoma may also occur, and well-known immunohistochemical markers, including cytokeratin 7 and 20, CDX2, p63, p40, chromogranin, and synaptophysin, are frequently used in differential diagnosis, along with recently discovered markers, such as SATB2, villin, INSM-1, etc. More importantly, abnormal expression of several proteins (e.g., HER2) or mutations in numerous genes (e.g., KRAS, mismatch repair genes etc.) helps to predict prognosis and/or response to targeted therapy in patients with gastrointestinal malignancy. In this chapter, diagnostic, prognostic, and predictive biomarkers in gastrointestinal carcinomas will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159(1):335–49.e15.

    Article  PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  3. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88.

    Article  Google Scholar 

  4. Arnold M, Rutherford MJ, Bardot A, Ferlay J, Andersson TM, Myklebust T, et al. Progress in cancer survival, mortality, and incidence in seven high-income countries 1995–2014 (ICBP SURVMARK-2): a population-based study. Lancet Oncol. 2019;20(11):1493–505.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Huynh JC, Schwab E, Ji J, Kim E, Joseph A, Hendifar A, et al. Recent advances in targeted therapies for advanced gastrointestinal malignancies. Cancers (Basel). 2020;12(5):1168.

    Article  CAS  Google Scholar 

  6. Arnold M, Ferlay J, van Berge Henegouwen MI, Soerjomataram I. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut. 2020;69(9):1564–71.

    Article  PubMed  Google Scholar 

  7. Ellis A, Risk JM, Maruthappu T, Kelsell DP. Tylosis with oesophageal cancer: diagnosis, management and molecular mechanisms. Orphanet J Rare Dis. 2015;10:126.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Alter BP. Fanconi’s anemia, transplantation, and cancer. Pediatr Transplant. 2005;9(Suppl 7):81–6.

    Article  PubMed  Google Scholar 

  9. Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541(7636):169–75.

    Article  CAS  Google Scholar 

  10. Businello G, Parente P, Mastracci L, Pennelli G, Traverso G, Milione M, et al. The pathologic and molecular landscape of esophageal squamous cell carcinogenesis. Cancers (Basel). 2020;12(8):2160.

    Article  CAS  Google Scholar 

  11. Sanchez-Danes A, Blanpain C. Deciphering the cells of origin of squamous cell carcinomas. Nat Rev Cancer. 2018;18(9):549–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kono K, Mimura K, Fujii H, Shabbir A, Yong WP, Jimmy SA. Potential therapeutic significance of HER-family in esophageal squamous cell carcinoma. Ann Thorac Cardiovasc Surg. 2012;18(6):506–13.

    Article  PubMed  Google Scholar 

  13. Sunpaweravong P, Sunpaweravong S, Puttawibul P, Mitarnun W, Zeng C, Barón AE, et al. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131(2):111–9.

    Article  CAS  PubMed  Google Scholar 

  14. Salem ME, Puccini A, Xiu J, Raghavan D, Lenz HJ, Korn WM, et al. Comparative molecular analyses of esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric adenocarcinoma. Oncologist. 2018;23(11):1319–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mukaida H, Yamamoto T, Hirai T, Toi M, Nakamura T, Wada T, et al. Expression of human epidermal growth factor and its receptor in esophageal cancer. Jpn J Surg. 1990;20(3):275–82.

    Article  CAS  PubMed  Google Scholar 

  16. Yoshida K, Kyo E, Tsuda T, Tsujino T, Ito M, Niimoto M, et al. EGF and TGF-alpha, the ligands of hyperproduced EGFR in human esophageal carcinoma cells, act as autocrine growth factors. Int J Cancer. 1990;45(1):131–5.

    Article  CAS  PubMed  Google Scholar 

  17. Wang Q, Zhu H, Xiao Z, Zhang W, Liu X, Zhang X, et al. Expression of epidermal growth factor receptor is an independent prognostic factor for esophageal squamous cell carcinoma. World J Surg Oncol. 2013;11:278.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Guo K, Wang WP, Jiang T, Wang JZ, Chen Z, Li Y, et al. Assessment of epidermal growth factor receptor mutation/copy number and K-ras mutation in esophageal cancer. J Thorac Dis. 2016;8(7):1753–63.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yu WW, Guo YM, Zhu M, Cai XW, Zhu ZF, Zhao WX, et al. Clinicopathological and prognostic significance of EGFR over-expression in esophageal squamous cell carcinoma: a meta-analysis. Hepatogastroenterology. 2011;58(106):426–31.

    CAS  PubMed  Google Scholar 

  20. Wang J, Yu JM, Jing SW, Guo Y, Wu YJ, Li N, et al. Relationship between EGFR over-expression and clinicopathologic characteristics in squamous cell carcinoma of the esophagus: a meta-analysis. Asian Pac J Cancer Prev. 2014;15(14):5889–93.

    Article  PubMed  Google Scholar 

  21. Yang YM, Hong P, Xu WW, He QY, Li B. Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther. 2020;5(1):229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mimura K, Kono K, Maruyama T, Watanabe M, Izawa S, Shiba S, et al. Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines. Int J Cancer. 2011;129(10):2408–16.

    Article  CAS  PubMed  Google Scholar 

  23. Mimura K, Kono K, Hanawa M, Kanzaki M, Nakao A, Ooi A, et al. Trastuzumab-mediated antibody-dependent cellular cytotoxicity against esophageal squamous cell carcinoma. Clin Cancer Res. 2005;11(13):4898–904.

    Article  CAS  PubMed  Google Scholar 

  24. Yoshino K, Motoyama S, Koyota S, Shibuya K, Sato Y, Sasaki T, et al. Identification of insulin-like growth factor 2 mRNA-binding protein 3 as a radioresistance factor in squamous esophageal cancer cells. Dis Esophagus. 2014;27(5):479–84.

    Article  CAS  PubMed  Google Scholar 

  25. Wakita A, Motoyama S, Sato Y, Nagaki Y, Fujita H, Terata K, et al. IGF2BP3 expression correlates with poor prognosis in esophageal squamous cell carcinoma. J Surg Res. 2020;259:137–44.

    Article  PubMed  CAS  Google Scholar 

  26. Tanaka T, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Katada T, et al. Vascular endothelial growth factor C (VEGF-C) in esophageal cancer correlates with lymph node metastasis and poor patient prognosis. J Exp Clin Cancer Res. 2010;29(1):83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Kumagai Y, Tachikawa T, Higashi M, Sobajima J, Takahashi A, Amano K, et al. Vascular endothelial growth factors C and D and lymphangiogenesis at the early stage of esophageal squamous cell carcinoma progression. Dis Esophagus. 2018;31(8).

    Google Scholar 

  28. Omoto I, Matsumoto M, Okumura H, Uchikado Y, Setoyama T, Kita Y, et al. Expression of vascular endothelial growth factor-C and vascular endothelial growth factor receptor-3 in esophageal squamous cell carcinoma. Oncol Lett. 2014;7(4):1027–32.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Idelevich E, Kashtan H, Klein Y, Buevich V, Baruch NB, Dinerman M, et al. Prospective phase II study of neoadjuvant therapy with cisplatin, 5-fluorouracil, and bevacizumab for locally advanced resectable esophageal cancer. Onkologie. 2012;35(7–8):427–31.

    Article  CAS  PubMed  Google Scholar 

  30. Bendell JC, Meluch A, Peyton J, Rubin M, Waterhouse D, Webb C, et al. A phase II trial of preoperative concurrent chemotherapy/radiation therapy plus bevacizumab/erlotinib in the treatment of localized esophageal cancer. Clin Adv Hematol Oncol. 2012;10(7):430–7.

    PubMed  Google Scholar 

  31. Guo W, Wang P, Li N, Shao F, Zhang H, Yang Z, et al. Prognostic value of PD-L1 in esophageal squamous cell carcinoma: a meta-analysis. Oncotarget. 2018;9(17):13920–33.

    Article  PubMed  Google Scholar 

  32. Okadome K, Baba Y, Nomoto D, Yagi T, Kalikawe R, Harada K, et al. Prognostic and clinical impact of PD-L2 and PD-L1 expression in a cohort of 437 oesophageal cancers. Br J Cancer. 2020;122(10):1535–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nomoto D, Baba Y, Okadome K, Yagi T, Kalikawe R, Kiyozumi Y, et al. Prognostic impact of PD-1 on tumor infiltrating lymphocytes in 433 resected esophageal cancers. Ann Thorac Surg. 2021; https://doi.org/10.1016/j.athoracsur.2021.01.013.

  34. Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, et al. Safety and antitumor activity of the anti-programmed death-1 antibody Pembrolizumab in patients with advanced esophageal carcinoma. J Clin Oncol. 2018;36(1):61–7.

    Article  CAS  PubMed  Google Scholar 

  35. Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, et al. Efficacy and safety of Pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546–50.

    Article  PubMed  Google Scholar 

  36. Kanaan C, Lorenzo D, Barret M, Audebourg A, Leblanc S, Chaussade S, et al. Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection. Virchows Arch. 2020;477(5):697–704.

    Article  CAS  PubMed  Google Scholar 

  37. Ishida H, Kasajima A, Fujishima F, Akaishi R, Ueki S, Yamazaki Y, et al. p16 in highly malignant esophageal carcinomas: the correlation with clinicopathological factors and human papillomavirus infection. Virchows Arch. 2021;478(2):219–29.

    Article  CAS  PubMed  Google Scholar 

  38. Brown IS, Fujii S, Kawachi H, Lam AK, Saito T. Oesophageal squamous cell carcinoma, NOS. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 48–53.

    Google Scholar 

  39. Bognár L, Hegedűs I, Bellyei S, Pozsgai É, Zoltán L, Gombos K, et al. Prognostic role of HPV infection in esophageal squamous cell carcinoma. Infect Agent Cancer. 2018;13:38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Farhadi M, Tahmasebi Z, Merat S, Kamangar F, Nasrollahzadeh D, Malekzadeh R. Human papillomavirus in squamous cell carcinoma of esophagus in a high-risk population. World J Gastroenterol. 2005;11(8):1200–3.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Melling N, Norrenbrock S, Kluth M, Simon R, Hube-Magg C, Steurer S, et al. p53 overexpression is a prognosticator of poor outcome in esophageal cancer. Oncol Lett. 2019;17(4):3826–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hatogai K, Fujii S, Kojima T, Daiko H, Nomura S, Doi T, et al. Large-scale comprehensive immunohistochemical biomarker analyses in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2017;143(11):2351–61.

    Article  CAS  PubMed  Google Scholar 

  43. Yu J, Zheng Y, Han XP, Peng H, Pang LJ, Li F, et al. Three-gene immunohistochemical panel predicts progression and unfavorable prognosis in esophageal squamous cell carcinoma. Hum Pathol. 2019;88:7–17.

    Article  CAS  PubMed  Google Scholar 

  44. Huang M, Jin J, Zhang F, Wu Y, Xu C, Ying L, et al. Non-disruptive mutation in TP53 DNA-binding domain is a beneficial factor of esophageal squamous cell carcinoma. Ann Transl Med. 2020;8(6):316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gao S, Zhao ZY, Zhang ZY, Zhang Y, Wu R. Prognostic value of microRNAs in esophageal carcinoma: a meta-analysis. Clin Transl Gastroenterol. 2018;9(11):203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lam AK, Kumarasinghe MP. Adenocarcinoma of the oesophagus and oesophagogastric junction NOS. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 38–43.

    Google Scholar 

  47. Driessen A, Nafteux P, Lerut T, Van Raemdonck D, De Leyn P, Filez L, et al. Identical cytokeratin expression pattern CK7+/CK20− in esophageal and cardiac cancer: etiopathological and clinical implications. Mod Pathol. 2004;17(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  48. Weimann A, Zimmermann M, Gross M, Slevogt H, Rieger A, Morawietz L. CDX2 and LI-cadherin expression in esophageal mucosa: use of both markers can facilitate the histologic diagnosis of Barrett’s esophagus and carcinoma. Int J Surg Pathol. 2010;18(5):330–7.

    Article  CAS  PubMed  Google Scholar 

  49. Lord RV, Brabender J, Wickramasinghe K, DeMeester SR, Holscher A, Schneider PM, et al. Increased CDX2 and decreased PITX1 homeobox gene expression in Barrett’s esophagus and Barrett’s-associated adenocarcinoma. Surgery. 2005;138(5):924–31.

    Article  PubMed  Google Scholar 

  50. van Lier MG, Bomhof FJ, Leendertse I, Flens M, Balk AT, Loffeld RJ. Cytokeratin phenotyping does not help in distinguishing oesophageal adenocarcinoma from cancer of the gastric cardia. J Clin Pathol. 2005;58(7):722–4.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Creemers A, Ebbing EA, Pelgrim TC, Lagarde SM, van Etten-Jamaludin FS, van Berge Henegouwen MI, et al. A systematic review and meta-analysis of prognostic biomarkers in resectable esophageal adenocarcinomas. Sci Rep. 2018;8(1):13281.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Prins MJ, Ruurda JP, van Diest PJ, van Hillegersberg R, Ten Kate FJ. The significance of the HER-2 status in esophageal adenocarcinoma for survival: an immunohistochemical and an in situ hybridization study. Ann Oncol. 2013;24(5):1290–7.

    Article  CAS  PubMed  Google Scholar 

  53. Janjigian YY, Werner D, Pauligk C, Steinmetz K, Kelsen DP, Jäger E, et al. Prognosis of metastatic gastric and gastroesophageal junction cancer by HER2 status: a European and USA international collaborative analysis. Ann Oncol. 2012;23(10):2656–62.

    Article  CAS  PubMed  Google Scholar 

  54. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  55. Stroes CI, Schokker S, Creemers A, Molenaar RJ, Hulshof M, van der Woude SO, et al. Phase II feasibility and biomarker study of neoadjuvant Trastuzumab and Pertuzumab with chemoradiotherapy for resectable human epidermal growth factor receptor 2-positive esophageal adenocarcinoma: TRAP study. J Clin Oncol. 2020;38(5):462–71.

    Article  CAS  PubMed  Google Scholar 

  56. Plum PS, Gebauer F, Krämer M, Alakus H, Berlth F, Chon SH, et al. HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma. BMC Cancer. 2019;19(1):38.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB III, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol. 2016;146(6):647–69.

    Article  PubMed  Google Scholar 

  58. Creemers A, Ebbing EA, Hooijer GKJ, Stap L, Jibodh-Mulder RA, Gisbertz SS, et al. The dynamics of HER2 status in esophageal adenocarcinoma. Oncotarget. 2018;9(42):26787–99.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Safran H, Winter KA, Wigle DA, DiPetrillo TA, Haddock MG, Hong TS, et al. Trastuzumab with trimodality treatment for esophageal adenocarcinoma with HER2 overexpression: NRG Oncology/RTOG 1010. J Clin Oncol. 2020;38(15_Suppl):4500.

    Article  Google Scholar 

  60. Yoshida H, Yamamoto N, Taniguchi H, Oda I, Katai H, Kushima R, et al. Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch. 2014;465(2):145–54.

    Article  CAS  PubMed  Google Scholar 

  61. Grin A, Brezden-Masley C, Bauer S, Streutker CJ. HER2 in situ hybridization in gastric and gastroesophageal adenocarcinoma: comparison of automated dual ISH to FISH. Appl Immunohistochem Mol Morphol. 2013;21(6):561–6.

    Article  CAS  PubMed  Google Scholar 

  62. García-García E, Gómez-Martín C, Angulo B, Conde E, Suárez-Gauthier A, Adrados M, et al. Hybridization for human epidermal growth factor receptor 2 testing in gastric carcinoma: a comparison of fluorescence in-situ hybridization with a novel fully automated dual-colour silver in-situ hybridization method. Histopathology. 2011;59(1):8–17.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Dutton SJ, Ferry DR, Blazeby JM, Abbas H, Dahle-Smith A, Mansoor W, et al. Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial. Lancet Oncol. 2014;15(8):894–904.

    Article  CAS  PubMed  Google Scholar 

  64. Petty RD, Dahle-Smith A, Stevenson DAJ, Osborne A, Massie D, Clark C, et al. Gefitinib and EGFR gene copy number aberrations in esophageal cancer. J Clin Oncol. 2017;35(20):2279–87.

    Article  CAS  PubMed  Google Scholar 

  65. Maron SB, Alpert L, Kwak HA, Lomnicki S, Chase L, Xu D, et al. Targeted therapies for targeted populations: anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma. Cancer Discov. 2018;8(6):696–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, et al. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):490–9.

    Article  CAS  PubMed  Google Scholar 

  67. Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Okines C, et al. Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14(6):481–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, et al. Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2–3 trial. Lancet Oncol. 2017;18(3):357–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31–9.

    Article  CAS  PubMed  Google Scholar 

  70. Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, et al. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):420–35.

    Article  CAS  PubMed  Google Scholar 

  71. Navarini D, Gurski RR, Madalosso CA, Aita L, Meurer L, Fornari F. Epidermal growth factor receptor expression in esophageal adenocarcinoma: relationship with tumor stage and survival after esophagectomy. Gastroenterol Res Pract. 2012;2012:941954.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chen M, Cai E, Huang J, Yu P, Li K. Prognostic value of vascular endothelial growth factor expression in patients with esophageal cancer: a systematic review and meta-analysis. Cancer Epidemiol Biomark Prev. 2012;21(7):1126–34.

    Article  CAS  Google Scholar 

  73. Farris AB III, Demicco EG, Le LP, Finberg KE, Miller J, Mandal R, et al. Clinicopathologic and molecular profiles of microsatellite unstable Barrett esophagus-associated adenocarcinoma. Am J Surg Pathol. 2011;35(5):647–55.

    Article  PubMed  Google Scholar 

  74. Imamura Y, Toihata T, Haraguchi I, Ogata Y, Takamatsu M, Kuchiba A, et al. Immunogenic characteristics of microsatellite instability-low esophagogastric junction adenocarcinoma based on clinicopathological, molecular, immunological and survival analyses. Int J Cancer. 2021;148(5):1260–75.

    Article  CAS  PubMed  Google Scholar 

  75. Däster S, Eppenberger-Castori S, Mele V, Schäfer HM, Schmid L, Weixler B, et al. Low expression of programmed death 1 (PD-1), PD-1 ligand 1 (PD-L1), and low CD8+ T lymphocyte infiltration identify a subgroup of patients with gastric and esophageal adenocarcinoma with severe prognosis. Front Med (Lausanne). 2020;7:144.

    Article  Google Scholar 

  76. Knief J, Lazar-Karsten P, Hummel R, Wellner U, Thorns C. PD-L1 expression in carcinoma of the esophagogastric junction is positively correlated with T-cell infiltration and overall survival. Pathol Res Pract. 2019;215(6):152402.

    Article  CAS  PubMed  Google Scholar 

  77. Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, et al. Efficacy and safety of Pembrolizumab or Pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571–80.

    Article  PubMed  Google Scholar 

  78. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.

    Article  CAS  PubMed  Google Scholar 

  79. Weinberg BA, Xiu J, Hwang JJ, Shields AF, Salem ME, Marshall JL. Immuno-oncology biomarkers for gastric and gastroesophageal junction adenocarcinoma: why PD-L1 testing may not be enough. Oncologist. 2018;23(10):1171–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Feber A, Xi L, Pennathur A, Gooding WE, Bandla S, Wu M, et al. MicroRNA prognostic signature for nodal metastases and survival in esophageal adenocarcinoma. Ann Thorac Surg. 2011;91(5):1523–30.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Mathé EA, Nguyen GH, Bowman ED, Zhao Y, Budhu A, Schetter AJ, et al. MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. Clin Cancer Res. 2009;15(19):6192–200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Hezova R, Kovarikova A, Srovnal J, Zemanova M, Harustiak T, Ehrmann J, et al. Diagnostic and prognostic potential of miR-21, miR-29c, miR-148 and miR-203 in adenocarcinoma and squamous cell carcinoma of esophagus. Diagn Pathol. 2015;10:42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Chen PC, Pan CC, Hsu WH, Ka HJ, Yang AH. Epstein-Barr virus-associated lymphoepithelioma-like carcinoma of the esophagus. Hum Pathol. 2003;34(4):407–11.

    Article  CAS  PubMed  Google Scholar 

  84. Terada T. Epstein-Barr virus associated lymphoepithelial carcinoma of the esophagus. Int J Clin Exp Med. 2013;6(3):219–26.

    PubMed  PubMed Central  Google Scholar 

  85. Hewitt LC, Inam IZ, Saito Y, Yoshikawa T, Quaas A, Hoelscher A, et al. Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: a large multi-centre study. Eur J Cancer. 2018;94:104–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Simchuk EJ, Low DE. Direct esophageal metastasis from a distant primary tumor is a submucosal process: a review of six cases. Dis Esophagus. 2001;14(3–4):247–50.

    Article  CAS  PubMed  Google Scholar 

  87. Seoung HG, Kim JH, Choi JC, Kim SM, Kim SS, Kim BH, et al. A case of papillary thyroid cancer recurring as an esophageal submucosal tumor. Chonnam Med J. 2012;48(1):60–4.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Fisher MS. Metastasis to the esophagus. Gastrointest Radiol. 1976;1(3):249–51.

    Article  CAS  PubMed  Google Scholar 

  89. Liu H, Shi J, Wilkerson ML, Lin F. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol. 2012;138(1):57–64.

    Article  PubMed  Google Scholar 

  90. Peng D, Guo Y, Chen H, Zhao S, Washington K, Hu T, et al. Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas. Sci Rep. 2017;7:40729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Aulakh KS, Chisholm CD, Smith DA, Speights VO. TTF-1 and napsin A do not differentiate metastatic lung adenocarcinomas from primary esophageal adenocarcinomas: proposal of a novel staining panel. Arch Pathol Lab Med. 2013;137(8):1094–8.

    Article  PubMed  Google Scholar 

  92. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21(11):4012.

    Article  CAS  PubMed Central  Google Scholar 

  93. Gullo I, van der Post RS, Carneiro F. Recent advances in the pathology of heritable gastric cancer syndromes. Histopathology. 2021;78(1):125–47.

    Article  PubMed  Google Scholar 

  94. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202–9.

    Article  CAS  Google Scholar 

  95. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392(6674):402–5.

    Article  CAS  PubMed  Google Scholar 

  96. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56.

    Article  CAS  PubMed  Google Scholar 

  97. Dabbs DJ. Diagnostic immunohistochemistry. In: Theranostic and genomic applications. 5th ed. Amsterdam: Elsevier; 2018.

    Google Scholar 

  98. Gonzalez RS, Messing S, Tu X, McMahon LA, Whitney-Miller CL. Immunohistochemistry as a surrogate for molecular subtyping of gastric adenocarcinoma. Hum Pathol. 2016;56:16–21.

    Article  CAS  PubMed  Google Scholar 

  99. van der Post RS, Gullo I, Oliveira C, Tang LH, Grabsch HI, O’Donovan M, et al. Histopathological, molecular, and genetic profile of hereditary diffuse gastric cancer: current knowledge and challenges for the future. Adv Exp Med Biol. 2016;908:371–91.

    Article  PubMed  Google Scholar 

  100. Cho SY, Park JW, Liu Y, Park YS, Kim JH, Yang H, et al. Sporadic early-onset diffuse gastric cancers have high frequency of somatic CDH1 alterations, but low frequency of somatic RHOA mutations compared with late-onset cancers. Gastroenterology. 2017;153(2):536–49.e26.

    Article  CAS  PubMed  Google Scholar 

  101. Blair VR, McLeod M, Carneiro F, Coit DG, D’Addario JL, van Dieren JM, et al. Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol. 2020;21(8):e386–e97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lee HE, Smyrk TC, Zhang L. Histologic and immunohistochemical differences between hereditary and sporadic diffuse gastric carcinoma. Hum Pathol. 2018;74:64–72.

    Article  CAS  PubMed  Google Scholar 

  103. Osada M, Aishima S, Hirahashi M, Takizawa N, Takahashi S, Nakamura K, et al. Combination of hepatocellular markers is useful for prognostication in gastric hepatoid adenocarcinoma. Hum Pathol. 2014;45(6):1243–50.

    Article  CAS  PubMed  Google Scholar 

  104. Ushiku T, Shinozaki-Ushiku A, Maeda D, Morita S, Fukayama M. Distinct expression pattern of claudin-6, a primitive phenotypic tight junction molecule, in germ cell tumours and visceral carcinomas. Histopathology. 2012;61(6):1043–56.

    Article  PubMed  Google Scholar 

  105. Murakami T, Yao T, Mitomi H, Morimoto T, Ueyama H, Matsumoto K, et al. Clinicopathologic and immunohistochemical characteristics of gastric adenocarcinoma with enteroblastic differentiation: a study of 29 cases. Gastric Cancer. 2016;19(2):498–507.

    Article  CAS  PubMed  Google Scholar 

  106. Yamazawa S, Ushiku T, Shinozaki-Ushiku A, Hayashi A, Iwasaki A, Abe H, et al. Gastric cancer with primitive enterocyte phenotype: an aggressive subgroup of intestinal-type adenocarcinoma. Am J Surg Pathol. 2017;41(7):989–97.

    Article  PubMed  Google Scholar 

  107. Zhu L, Li Z, Wang Y, Zhang C, Liu Y, Qu X. Microsatellite instability and survival in gastric cancer: a systematic review and meta-analysis. Mol Clin Oncol. 2015;3(3):699–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–58.

    Article  CAS  PubMed  Google Scholar 

  109. Setia N, Agoston AT, Han HS, Mullen JT, Duda DG, Clark JW, et al. A protein and mRNA expression-based classification of gastric cancer. Mod Pathol. 2016;29(7):772–84.

    Article  CAS  PubMed  Google Scholar 

  110. Grogg KL, Lohse CM, Pankratz VS, Halling KC, Smyrk TC. Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival. Mod Pathol. 2003;16(7):641–51.

    Article  PubMed  Google Scholar 

  111. Akazawa Y, Saito T, Hayashi T, Yanai Y, Tsuyama S, Akaike K, et al. Next-generation sequencing analysis for gastric adenocarcinoma with enteroblastic differentiation: emphasis on the relationship with hepatoid adenocarcinoma. Hum Pathol. 2018;78:79–88.

    Article  CAS  PubMed  Google Scholar 

  112. Fujimoto M, Matsuzaki I, Nishino M, Iwahashi Y, Warigaya K, Kojima F, et al. HER2 is frequently overexpressed in hepatoid adenocarcinoma and gastric carcinoma with enteroblastic differentiation: a comparison of 35 cases to 334 gastric carcinomas of other histological types. J Clin Pathol. 2018;71(7):600–7.

    Article  CAS  PubMed  Google Scholar 

  113. Tsuruta S, Ohishi Y, Fujiwara M, Ihara E, Ogawa Y, Oki E, et al. Gastric hepatoid adenocarcinomas are a genetically heterogenous group; most tumors show chromosomal instability, but MSI tumors do exist. Hum Pathol. 2019;88:27–38.

    Article  PubMed  Google Scholar 

  114. Brien TP, Depowski PL, Sheehan CE, Ross JS, McKenna BJ. Prognostic factors in gastric cancer. Mod Pathol. 1998;11(9):870–7.

    CAS  PubMed  Google Scholar 

  115. Boers JE, Meeuwissen H, Methorst N. HER2 status in gastro-oesophageal adenocarcinomas assessed by two rabbit monoclonal antibodies (SP3 and 4B5) and two in situ hybridization methods (FISH and SISH). Histopathology. 2011;58(3):383–94.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kim WH, Gomez-Izquierdo L, Vilardell F, Chu KM, Soucy G, Dos Santos LV, et al. HER2 status in gastric and gastroesophageal junction cancer: results of the large, multinational HER-EAGLE study. Appl Immunohistochem Mol Morphol. 2018;26(4):239–45.

    Article  CAS  PubMed  Google Scholar 

  117. Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476–84.

    Article  PubMed  CAS  Google Scholar 

  118. Lei YY, Huang JY, Zhao QR, Jiang N, Xu HM, Wang ZN, et al. The clinicopathological parameters and prognostic significance of HER2 expression in gastric cancer patients: a meta-analysis of literature. World J Surg Oncol. 2017;15(1):68.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Wang Y, He L, Cheng Y. An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis. Clin Transl Oncol. 2018;20(2):212–20.

    Article  PubMed  CAS  Google Scholar 

  120. Lieto E, Ferraraccio F, Orditura M, Castellano P, Mura AL, Pinto M, et al. Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients. Ann Surg Oncol. 2008;15(1):69–79.

    Article  PubMed  Google Scholar 

  121. Fard SS, Saliminejad K, Sotoudeh M, Soleimanifard N, Kouchaki S, Yazdanbod M, et al. The correlation between EGFR and androgen receptor pathways: a novel potential prognostic marker in gastric cancer. Anti Cancer Agents Med Chem. 2019;19(17):2097–107.

    Article  CAS  Google Scholar 

  122. Wang C, Xi W, Ji J, Cai Q, Zhao Q, Jiang J, et al. The prognostic value of HGF-c-MET signaling pathway in gastric cancer: a study based on TCGA and GEO databases. Int J Med Sci. 2020;17(13):1946–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Erichsen R, Kelsh MA, Oliner KS, Nielsen KB, Frøslev T, Lænkholm AV, et al. Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: a Danish cohort study. Ann Epidemiol. 2016;26(7):500–3.

    Article  PubMed  Google Scholar 

  124. Pant S, Patel M, Kurkjian C, Hemphill B, Flores M, Thompson D, et al. A phase II study of the c-Met inhibitor Tivantinib in combination with FOLFOX for the treatment of patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal junction, or stomach. Cancer Investig. 2017;35(7):463–72.

    Article  Google Scholar 

  125. Sanchez-Vega F, Hechtman JF, Castel P, Ku GY, Tuvy Y, Won H, et al. EGFR and MET amplifications determine response to HER2 inhibition in ERBB2-amplified esophagogastric cancer. Cancer Discov. 2019;9(2):199–209.

    Article  CAS  PubMed  Google Scholar 

  126. Smyth EC, Vlachogiannis G, Hedayat S, Harbery A, Hulkki-Wilson S, Salati M, et al. EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers. Gut. 2021;70(9):1632–41.

    Article  CAS  PubMed  Google Scholar 

  127. Quintero Aldana G, Salgado M, Candamio S, Méndez JC, Jorge M, Reboredo M, et al. First-line panitumumab plus docetaxel and cisplatin in advanced gastric and gastro-oesophageal junction adenocarcinoma: results of a phase II trial. Clin Transl Oncol. 2020;22(4):495–502.

    Article  CAS  PubMed  Google Scholar 

  128. Yang L, Dong XZ, Xing XX, Cui XH, Li L, Zhang L. Efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in treatment of advanced gastric cancer or gastroesophageal junction cancer: a meta-analysis. World J Gastrointest Oncol. 2020;12(11):1346–63.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Yun S, Koh J, Nam SK, Kwak Y, Ahn SH, Do Park J, et al. Immunoscore is a strong predictor of survival in the prognosis of stage II/III gastric cancer patients following 5-FU-based adjuvant chemotherapy. Cancer Immunol Immunother. 2021;70(2):431–41.

    Article  CAS  PubMed  Google Scholar 

  130. Xing X, Guo J, Ding G, Li B, Dong B, Feng Q, et al. Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology. 2018;7(3):e1356144.

    Article  PubMed  Google Scholar 

  131. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123–33.

    Article  CAS  PubMed  Google Scholar 

  132. Ahadi A. A systematic review of microRNAs as potential biomarkers for diagnosis and prognosis of gastric cancer. Immunogenetics. 2021;73(2):155–61.

    Article  CAS  PubMed  Google Scholar 

  133. Taheri M, Shoorei H, Anamag FT, Ghafouri-Fard S, Dinger ME. LncRNAs and miRNAs participate in determination of response of cancer cells to cisplatin. Exp Mol Pathol. 2021;2021:104602.

    Article  CAS  Google Scholar 

  134. Gao Y, Zhang K, Xi H, Cai A, Wu X, Cui J, et al. Diagnostic and prognostic value of circulating tumor DNA in gastric cancer: a meta-analysis. Oncotarget. 2017;8(4):6330–40.

    Article  PubMed  Google Scholar 

  135. Graham RP, Nair AA, Davila JI, Jin L, Jen J, Sukov WR, et al. Gastroblastoma harbors a recurrent somatic MALAT1-GLI1 fusion gene. Mod Pathol. 2017;30(10):1443–52.

    Article  CAS  PubMed  Google Scholar 

  136. Montgomery EA. Gastroblastoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 102–3.

    Google Scholar 

  137. Kleist B, Lasota J, Miettinen M. Gastrointestinal stromal tumor and gastric adenocarcinoma collision tumors. Hum Pathol. 2010;41(7):1034–9.

    Article  PubMed  Google Scholar 

  138. Dei Tos AP, Hornick JL, Miettinen M. Gastrointestinal stromal tumour. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 439–43.

    Google Scholar 

  139. Şahin S, Ekinci Ö, Seçkin S, Dursun A. The diagnostic and prognostic utility of DOG1 expression on gastrointestinal stromal tumors. Turk Patoloji Derg. 2017;33(1):1–8.

    PubMed  Google Scholar 

  140. Baniak N, Lee L, Zhou C, Young S, Yu D. An epithelioid gastrointestinal stromal tumor of the stomach with strong expression of keratin: clinicopathologic correlation and follow-up post-imatinib therapy. Appl Immunohistochem Mol Morphol. 2019;27(9):e85–90.

    Article  CAS  PubMed  Google Scholar 

  141. Oda, Kondo H, Yamao T, Saito D, Ono H, Gotoda T, et al. Metastatic tumors to the stomach: analysis of 54 patients diagnosed at endoscopy and 347 autopsy cases. Endoscopy. 2001;33(6):507–10.

    Article  CAS  PubMed  Google Scholar 

  142. Namikawa T, Hanazaki K. Clinicopathological features and treatment outcomes of metastatic tumors in the stomach. Surg Today. 2014;44(8):1392–9.

    Article  PubMed  Google Scholar 

  143. Takamori H, Kanemitsu K, Tsuji T, Kusano S, Chikamoto A, Okuma T, et al. Metastatic gastric tumor secondary to pancreatic adenocarcinoma. J Gastroenterol. 2005;40(2):209–12.

    Article  PubMed  Google Scholar 

  144. Almubarak MM, Laé M, Cacheux W, de Cremoux P, Pierga JY, Reyal F, et al. Gastric metastasis of breast cancer: a single centre retrospective study. Dig Liver Dis. 2011;43(10):823–7.

    Article  PubMed  Google Scholar 

  145. Unlu M, Canda T, Sevinc A, Harmancioglu O, Saydam S, Kocdor MA, et al. Staining features of GCDFP-15, ALA, CK7, and CK20 in primary and metastatic breast cancers. Turk Patoloji Derg. 2009;25(3):78–84.

    Google Scholar 

  146. Hui Y, Wang Y, Nam G, Fanion J, Sturtevant A, Lombardo KA, et al. Differentiating breast carcinoma with signet ring features from gastrointestinal signet ring carcinoma: assessment of immunohistochemical markers. Hum Pathol. 2018;77:11–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ryu WS, Kim JH, Jang YJ, Park SS, Um JW, Park SH, et al. Expression of estrogen receptors in gastric cancer and their clinical significance. J Surg Oncol. 2012;106(4):456–61.

    Article  CAS  PubMed  Google Scholar 

  148. Yi JH, Do IG, Jang J, Kim ST, Kim KM, Park SH, et al. Anti-tumor efficacy of fulvestrant in estrogen receptor positive gastric cancer. Sci Rep. 2014;4:7592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nguyen MD, Plasil B, Wen P, Frankel WL. Mucin profiles in signet-ring cell carcinoma. Arch Pathol Lab Med. 2006;130(6):799–804.

    Article  CAS  PubMed  Google Scholar 

  150. Salto-Tellez M, Rugge M. Tumours of the small intestine and ampulla: introduction. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 116–7.

    Google Scholar 

  151. Barsouk A, Rawla P, Barsouk A, Thandra KC. Epidemiology of cancers of the small intestine: trends, risk factors, and prevention. Med Sci (Basel). 2019;7(3):46.

    CAS  Google Scholar 

  152. Aparicio T, Henriques J, Manfredi S, Tougeron D, Bouché O, Pezet D, et al. Small bowel adenocarcinoma: results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients. Int J Cancer. 2020;147(4):967–77.

    Article  CAS  PubMed  Google Scholar 

  153. Adsay V, Nagtegaal ID, Reid MD. Non-ampullary adenocarcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 124–6.

    Google Scholar 

  154. Alvi MA, McArt DG, Kelly P, Fuchs MA, Alderdice M, McCabe CM, et al. Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility. Oncotarget. 2015;6(25):20863–74.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Schrock AB, Devoe CE, McWilliams R, Sun J, Aparicio T, Stephens PJ, et al. Genomic profiling of small-bowel adenocarcinoma. JAMA Oncol. 2017;3(11):1546–53.

    Article  PubMed  PubMed Central  Google Scholar 

  156. Xue Y, Vanoli A, Balci S, Reid MM, Saka B, Bagci P, et al. Non-ampullary-duodenal carcinomas: clinicopathologic analysis of 47 cases and comparison with ampullary and pancreatic adenocarcinomas. Mod Pathol. 2017;30(2):255–66.

    Article  CAS  PubMed  Google Scholar 

  157. Chen ZM, Ritter JH, Wang HL. Differential expression of alpha-methylacyl coenzyme A racemase in adenocarcinomas of the small and large intestines. Am J Surg Pathol. 2005;29(7):890–6.

    Article  PubMed  Google Scholar 

  158. Kim CJ, Baruch-Oren T, Lin F, Fan XS, Yang XJ, Wang HL. Value of SATB2 immunostaining in the distinction between small intestinal and colorectal adenocarcinomas. J Clin Pathol. 2016;69(12):1046–50.

    Article  CAS  PubMed  Google Scholar 

  159. Neri G, Arpa G, Guerini C, Grillo F, Lenti MV, Giuffrida P, et al. Small bowel adenocarcinomas featuring special AT-rich sequence-binding protein 2 (SATB2) expression and a colorectal cancer-like immunophenotype: a potential diagnostic pitfall. Cancers (Basel). 2020;12(11):3441.

    Article  CAS  Google Scholar 

  160. Vanoli A, Di Sabatino A, Furlan D, Klersy C, Grillo F, Fiocca R, et al. Small bowel carcinomas in coeliac or Crohn’s disease: clinico-pathological, molecular, and prognostic features. A study from the Small Bowel Cancer Italian Consortium. J Crohns Colitis. 2017;11(8):942–53.

    Article  PubMed  Google Scholar 

  161. Rizzo F, Vanoli A, Sahnane N, Cerutti R, Trapani D, Rinaldi A, et al. Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes. Virchows Arch. 2020;476(5):711–23.

    Article  CAS  PubMed  Google Scholar 

  162. Vanoli A, Di Sabatino A, Martino M, Klersy C, Grillo F, Mescoli C, et al. Small bowel carcinomas in celiac or Crohn’s disease: distinctive histophenotypic, molecular and histogenetic patterns. Mod Pathol. 2017;30(10):1453–66.

    Article  CAS  PubMed  Google Scholar 

  163. Nagtegaal ID, Arends MJ, Salto-Tellez M. Colorectal adenocarcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 177–87.

    Google Scholar 

  164. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.

    Article  CAS  Google Scholar 

  165. Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Hinoi T, Tani M, Lucas PC, Caca K, Dunn RL, Macri E, et al. Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol. 2001;159(6):2239–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kim JH, Rhee YY, Bae JM, Cho NY, Kang GH. Loss of CDX2/CK20 expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer. Am J Surg Pathol. 2013;37(10):1532–41.

    Article  PubMed  Google Scholar 

  168. Kandalaft PL, Gown AM. Practical applications in immunohistochemistry: carcinomas of unknown primary site. Arch Pathol Lab Med. 2016;140(6):508–23.

    Article  CAS  PubMed  Google Scholar 

  169. Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, et al. Practical immunohistochemistry in neoplastic pathology of the gastrointestinal tract, liver, biliary tract, and pancreas. Arch Pathol Lab Med. 2017;141(9):1155–80.

    Article  CAS  PubMed  Google Scholar 

  170. Liu F, Gao Z, Shen D, Zhao H, Wang C, Ye Y, et al. Significance of SATB2 expression in colon cancer and its differential diagnosis in digestive tract adenocarcinoma and ovarian primary and metastatic carcinoma. Pathol Res Pract. 2019;2019:152430.

    Article  CAS  Google Scholar 

  171. Ma C, Olevian DC, Lowenthal BM, Jayachandran P, Kozak MM, Chang DT, et al. Loss of SATB2 expression in colorectal carcinoma is associated with DNA mismatch repair protein deficiency and BRAF mutation. Am J Surg Pathol. 2018;42(10):1409–17.

    Article  PubMed  Google Scholar 

  172. Fiehn AM, Grauslund M, Glenthøj A, Melchior LC, Vainer B, Willemoe GL. Medullary carcinoma of the colon: can the undifferentiated be differentiated? Virchows Arch. 2015;466(1):13–20.

    Article  PubMed  Google Scholar 

  173. Winn B, Tavares R, Fanion J, Noble L, Gao J, Sabo E, et al. Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation. Hum Pathol. 2009;40(3):398–404.

    Article  CAS  PubMed  Google Scholar 

  174. Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A. SWI/SNF complex-deficient undifferentiated/Rhabdoid carcinomas of the gastrointestinal tract: a series of 13 cases highlighting mutually exclusive loss of SMARCA4 and SMARCA2 and frequent co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 2016;40(4):544–53.

    Article  PubMed  Google Scholar 

  175. Wang J, Andrici J, Sioson L, Clarkson A, Sheen A, Farzin M, et al. Loss of INI1 expression in colorectal carcinoma is associated with high tumor grade, poor survival, BRAFV600E mutation, and mismatch repair deficiency. Hum Pathol. 2016;55:83–90.

    Article  CAS  PubMed  Google Scholar 

  176. Gupta R, Sinha S, Paul RN. The impact of microsatellite stability status in colorectal cancer. Curr Probl Cancer. 2018;42(6):548–59.

    Article  PubMed  Google Scholar 

  177. Wang QX, Qu CH, Gao YH, Ding PR, Yun JP, Xie D, et al. The degree of microsatellite instability predicts response to PD-1 blockade immunotherapy in mismatch repair-deficient/microsatellite instability-high colorectal cancers. Exp Hematol Oncol. 2021;10(1):2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Cohen R, Bennouna J, Meurisse A, Tournigand C, De La Fouchardière C, Tougeron D, et al. RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study. J Immunother Cancer. 2020;8(2):e001499.

    Article  PubMed  PubMed Central  Google Scholar 

  179. Marginean EC, Melosky B. Is there a role for programmed death ligand-1 testing and immunotherapy in colorectal cancer with microsatellite instability? Part I-Colorectal cancer: microsatellite instability, testing, and clinical implications. Arch Pathol Lab Med. 2018;142(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  180. NCCN Guidelines CCS, version I.2018. https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed on 1 Jun 2019.

  181. Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn. 2008;10(4):293–300.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Bartley AN, Hamilton SR, Alsabeh R, Ambinder EP, Berman M, Collins E, et al. Template for reporting results of biomarker testing of specimens from patients with carcinoma of the colon and rectum. 2014. Available from: https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates. Accessed on 19 Mar 2021.

  183. Zavodna K, Krivulcik T, Bujalkova MG, Slamka T, Martinicky D, Ilencikova D, et al. Partial loss of heterozygosity events at the mutated gene in tumors from MLH1/MSH2 large genomic rearrangement carriers. BMC Cancer. 2009;9:405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. 1998;95(12):6870–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bettstetter M, Dechant S, Ruemmele P, Grabowski M, Keller G, Holinski-Feder E, et al. Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res. 2007;13(11):3221–8.

    Article  CAS  PubMed  Google Scholar 

  186. Domingo E, Laiho P, Ollikainen M, Pinto M, Wang L, French AJ, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet. 2004;41(9):664–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Deng G, Bell I, Crawley S, Gum J, Terdiman JP, Allen BA, et al. BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res. 2004;10(1 Pt 1):191–5.

    Article  CAS  PubMed  Google Scholar 

  188. Jin M, Hampel H, Zhou X, Schunemann L, Yearsley M, Frankel WL. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol. 2013;140(2):177–83.

    Article  CAS  PubMed  Google Scholar 

  189. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34.

    Article  CAS  PubMed  Google Scholar 

  190. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–9.

    Article  CAS  PubMed  Google Scholar 

  191. Therkildsen C, Bergmann TK, Henrichsen-Schnack T, Ladelund S, Nilbert M. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis. Acta Oncol. 2014;53(7):852–64.

    Article  CAS  PubMed  Google Scholar 

  192. Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(13):1453–86.

    Article  CAS  PubMed  Google Scholar 

  193. Mao C, Yang ZY, Hu XF, Chen Q, Tang JL. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2012;23(6):1518–25.

    Article  CAS  PubMed  Google Scholar 

  194. Graham DM, Appelman HD. Crohn’s-like lymphoid reaction and colorectal carcinoma: a potential histologic prognosticator. Mod Pathol. 1990;3(3):332–5.

    CAS  PubMed  Google Scholar 

  195. Väyrynen JP, Sajanti SA, Klintrup K, Mäkelä J, Herzig KH, Karttunen TJ, et al. Characteristics and significance of colorectal cancer associated lymphoid reaction. Int J Cancer. 2014;134(9):2126–35.

    Article  PubMed  CAS  Google Scholar 

  196. Ueno H, Hashiguchi Y, Shimazaki H, Shinto E, Kajiwara Y, Nakanishi K, et al. Objective criteria for Crohn-like lymphoid reaction in colorectal cancer. Am J Clin Pathol. 2013;139(4):434–41.

    Article  CAS  PubMed  Google Scholar 

  197. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    Article  CAS  PubMed  Google Scholar 

  198. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128–39.

    Article  PubMed  Google Scholar 

  199. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Overman MJ, Kopetz S, McDermott RS, Leach J, Lonardi S, Lenz H-J, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results. J Clin Oncol. 2016;34(15_Suppl):3501.

    Article  Google Scholar 

  201. Ahtiainen M, Wirta EV, Kuopio T, Seppälä T, Rantala J, Mecklin JP, et al. Combined prognostic value of CD274 (PD-L1)/PDCDI (PD-1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status. Mod Pathol. 2019;32(6):866–83.

    Article  CAS  PubMed  Google Scholar 

  202. Li Y, Liang L, Dai W, Cai G, Xu Y, Li X, et al. Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer. Mol Cancer. 2016;15(1):55.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Berntsson J, Eberhard J, Nodin B, Leandersson K, Larsson AH, Jirström K. Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: relationship with sidedness and prognosis. Oncoimmunology. 2018;7(8):e1465165.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Lebe B, Sarioğlu S, Sökmen S, Ellidokuz H, Füzün M, Küpelioğlu A. The clinical significance of p53, p21, and p27 expressions in rectal carcinoma. Appl Immunohistochem Mol Morphol. 2005;13(1):38–44.

    Article  CAS  PubMed  Google Scholar 

  205. Ogino S, Nosho K, Shima K, Baba Y, Irahara N, Kirkner GJ, et al. p21 expression in colon cancer and modifying effects of patient age and body mass index on prognosis. Cancer Epidemiol Biomark Prev. 2009;18(9):2513–21.

    Article  CAS  Google Scholar 

  206. Al-Maghrabi J, Al-Ahwal M, Buhmeida A, Syrjänen K, Sibyani A, Emam E, et al. Expression of cell cycle regulators p21 and p27 as predictors of disease outcome in colorectal carcinoma. J Gastrointest Cancer. 2012;43(2):279–87.

    Article  CAS  PubMed  Google Scholar 

  207. Sökmen S, Sarioglu S, Füzün M, Terzi C, Küpelioglu A, Aslan B. Prognostic significance of angiogenesis in rectal cancer: a morphometric investigation. Anticancer Res. 2001;21(6b):4341–8.

    PubMed  Google Scholar 

  208. Cavdar Z, Canda AE, Terzi C, Sarioglu S, Fuzun M, Oktay G. Role of gelatinases (matrix metalloproteinases 2 and 9), vascular endothelial growth factor and endostatin on clinicopathological behaviour of rectal cancer. Colorectal Dis. 2011;13(2):154–60.

    Article  CAS  PubMed  Google Scholar 

  209. Sis B, Sağol O, Küpelioğlu A, Sokmen S, Terzi C, Fuzun M, et al. Prognostic significance of matrix metalloproteinase-2, cathepsin D, and tenascin-C expression in colorectal carcinoma. Pathol Res Pract. 2004;200(5):379–87.

    Article  CAS  PubMed  Google Scholar 

  210. Said AH, Raufman JP, Xie G. The role of matrix metalloproteinases in colorectal cancer. Cancers (Basel). 2014;6(1):366–75.

    Article  Google Scholar 

  211. Jones RP, Pugh SA, Graham J, Primrose JN, Barriuso J. Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Eur J Cancer. 2021;144:368–81.

    Article  CAS  PubMed  Google Scholar 

  212. Perdyan A, Spychalski P, Kacperczyk J, Rostkowska O, Kobiela J. Circulating tumor DNA in KRAS positive colorectal cancer patients as a prognostic factor - a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2020;154:103065.

    Article  PubMed  Google Scholar 

  213. Spindler KG, Boysen AK, Pallisgård N, Johansen JS, Tabernero J, Sørensen MM, et al. Cell-free DNA in metastatic colorectal cancer: a systematic review and meta-analysis. Oncologist. 2017;22(9):1049–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Sabarimurugan S, Madhav MR, Kumarasamy C, Gupta A, Baxi S, Krishnan S, et al. Prognostic value of MicroRNAs in stage II colorectal cancer patients: a systematic review and meta-analysis. Mol Diagn Ther. 2020;24(1):15–30.

    Article  CAS  PubMed  Google Scholar 

  215. Marx A, Simon P, Simon R, Mirlacher M, Izbicki JR, Yekebas E, et al. AMACR expression in colorectal cancer is associated with left-sided tumor localization. Virchows Arch. 2008;453(3):243–8.

    Article  CAS  PubMed  Google Scholar 

  216. Zhou M, Chinnaiyan AM, Kleer CG, Lucas PC, Rubin MA. Alpha-Methylacyl-CoA racemase: a novel tumor marker over-expressed in several human cancers and their precursor lesions. Am J Surg Pathol. 2002;26(7):926–31.

    Article  PubMed  Google Scholar 

  217. Misdraji J, Carr NJ, Pai RK. Appendiceal mucinous neoplasm. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 144–6.

    Google Scholar 

  218. Misdraji J, Yantiss RK, Graeme-Cook FM, Balis UJ, Young RH. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003;27(8):1089–103.

    Article  PubMed  Google Scholar 

  219. Singhi AD, Davison JM, Choudry HA, Pingpank JF, Ahrendt SA, Holtzman MP, et al. GNAS is frequently mutated in both low-grade and high-grade disseminated appendiceal mucinous neoplasms but does not affect survival. Hum Pathol. 2014;45(8):1737–43.

    Article  CAS  PubMed  Google Scholar 

  220. Chu PG, Chung L, Weiss LM, Lau SK. Determining the site of origin of mucinous adenocarcinoma: an immunohistochemical study of 175 cases. Am J Surg Pathol. 2011;35(12):1830–6.

    Article  PubMed  Google Scholar 

  221. Schmoeckel E, Kirchner T, Mayr D. SATB2 is a supportive marker for the differentiation of a primary mucinous tumor of the ovary and an ovarian metastasis of a low-grade appendiceal mucinous neoplasm (LAMN): a series of seven cases. Pathol Res Pract. 2018;214(3):426–30.

    Article  CAS  PubMed  Google Scholar 

  222. Moh M, Krings G, Ates D, Aysal A, Kim GE, Rabban JT. SATB2 expression distinguishes ovarian metastases of colorectal and appendiceal origin from primary ovarian tumors of mucinous or endometrioid type. Am J Surg Pathol. 2016;40(3):419–32.

    Article  PubMed  Google Scholar 

  223. Aldaoud N, Erashdi M, AlKhatib S, Abdo N, Al-Mohtaseb A, Graboski-Bauer A. The utility of PAX8 and SATB2 immunohistochemical stains in distinguishing ovarian mucinous neoplasms from colonic and appendiceal mucinous neoplasm. BMC Res Notes. 2019;12(1):770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Yanai Y, Saito T, Hayashi T, Akazawa Y, Yatagai N, Tsuyama S, et al. Molecular and clinicopathological features of appendiceal mucinous neoplasms. Virchows Arch. 2021;478(3):413–26.

    Article  CAS  PubMed  Google Scholar 

  225. Zhu X, Salhab M, Tomaszewicz K, Meng X, Mathew C, Bathini V, et al. Heterogeneous mutational profile and prognosis conferred by TP53 mutations in appendiceal mucinous neoplasms. Hum Pathol. 2019;85:260–9.

    Article  CAS  PubMed  Google Scholar 

  226. Davison JM, Hartman DA, Singhi AD, Choudry HA, Ahrendt SA, Zureikat AH, et al. Loss of SMAD4 protein expression is associated with high tumor grade and poor prognosis in disseminated appendiceal mucinous neoplasms. Am J Surg Pathol. 2014;38(5):583–92.

    Article  PubMed  Google Scholar 

  227. Misdraji J, Carr NJ, Pai RK. Appendiceal adenocarcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 147–8.

    Google Scholar 

  228. Tokunaga R, Xiu J, Johnston C, Goldberg RM, Philip PA, Seeber A, et al. Molecular profiling of appendiceal adenocarcinoma and comparison with right-sided and left-sided colorectal cancer. Clin Cancer Res. 2019;25(10):3096–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ritterhouse LL, Wu EY, Kim WG, Dillon DA, Hirsch MS, Sholl LM, et al. Loss of SMAD4 protein expression in gastrointestinal and extra-gastrointestinal carcinomas. Histopathology. 2019;75(4):546–51.

    Article  PubMed  Google Scholar 

  230. Raghav KP, Shetty AV, Kazmi SM, Zhang N, Morris J, Taggart M, et al. Impact of molecular alterations and targeted therapy in appendiceal adenocarcinomas. Oncologist. 2013;18(12):1270–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Chang MS, Byeon SJ, Yoon SO, Kim BH, Lee HS, Kang GH, et al. Leptin, MUC2 and mTOR in appendiceal mucinous neoplasms. Pathobiology. 2012;79(1):45–53.

    Article  CAS  PubMed  Google Scholar 

  232. Misdraji J, Carr NJ, Pai RK. Appendiceal goblet cell adenocarcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 149–51.

    Google Scholar 

  233. Reid MD, Basturk O, Shaib WL, Xue Y, Balci S, Choi HJ, et al. Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases. Mod Pathol. 2016;29(10):1243–53.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Reid MD, Pehlivanoglu B, Xue Y, Memis B, Robinson BS, Toussaint MA, et al. Adenocarcinoma ex-goblet cell carcinoid is not a neuroendocrine neoplasm: immunoprofiling of 60 cases further establishes its identity as a distinct (appendiceal type) of adenocarcinoma (Abstract). Mod Pathol. 2018;31:831.

    Google Scholar 

  235. Yang C, Gonzalez I, Zhang L, Cao D. Neuroendocrine markers insulinoma-associated protein 1, chromogranin, synaptophysin, and CD56 show rare positivity in adenocarcinoma ex-goblet cell carcinoids. Gastroenterology Res. 2019;12(3):120–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Yang C, Sun L, Zhang L, Zhou L, Niu D, Cao W, et al. SATB2 shows different profiles between appendiceal adenocarcinomas ex goblet cell carcinoids and appendiceal/colorectal conventional adenocarcinomas: an immunohistochemical study with comparison to CDX2. Gastroenterology Res. 2018;11(3):221–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Jesinghaus M, Konukiewitz B, Foersch S, Stenzinger A, Steiger K, Muckenhuber A, et al. Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix. Mod Pathol. 2018;31(5):829–39.

    Article  CAS  PubMed  Google Scholar 

  238. Arai H, Baca Y, Battaglin F, Kawanishi N, Wang J, Soni S, et al. Molecular characterization of appendiceal goblet cell carcinoid. Mol Cancer Ther. 2020;19(12):2634–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Johncilla M, Stachler M, Misdraji J, Lisovsky M, Yozu M, Lindeman N, et al. Mutational landscape of goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix is distinct from typical carcinoids and colorectal adenocarcinomas. Mod Pathol. 2018;31(6):989–96.

    Article  CAS  PubMed  Google Scholar 

  240. Yoon WJ, Yoon YB, Kim YJ, Ryu JK, Kim YT. Secondary appendiceal tumors: a review of 139 cases. Gut Liver. 2010;4(3):351–6.

    Article  PubMed  PubMed Central  Google Scholar 

  241. Chiesa-Vottero A. CDX2, SATB2, GATA3, TTF1, and PAX8 immunohistochemistry in Krukenberg tumors. Int J Gynecol Pathol. 2020;39(2):170–7.

    Article  CAS  PubMed  Google Scholar 

  242. Graham RP. Anal squamous cell carcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. IARC Press, Lyon, France; 2019. p. 205–7.

    Google Scholar 

  243. Aldersley J, Lorenz DR, Misra V, Uno H, Gabuzda D. Increased risk of anal squamous cell carcinoma in HIV-positive men with prior hepatitis B virus infection. AIDS. 2019;33(1):145–52.

    Article  PubMed  Google Scholar 

  244. Beaugerie L, Carrat F, Nahon S, Zeitoun JD, Sabaté JM, Peyrin-Biroulet L, et al. High risk of anal and rectal cancer in patients with anal and/or perianal Crohn’s disease. Clin Gastroenterol Hepatol. 2018;16(6):892–9.e2.

    Article  PubMed  Google Scholar 

  245. Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012;13(5):487–500.

    Article  PubMed  Google Scholar 

  246. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59–67.

    Article  PubMed  Google Scholar 

  247. Casadei Gardini A, Capelli L, Ulivi P, Giannini M, Freier E, Tamberi S, et al. KRAS, BRAF and PIK3CA status in squamous cell anal carcinoma (SCAC). PLoS One. 2014;9(3):e92071.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Cacheux W, Tsantoulis P, Briaux A, Vacher S, Mariani P, Richard-Molard M, et al. Array comparative genomic hybridization identifies high level of PI3K/Akt/mTOR pathway alterations in anal cancer recurrences. Cancer Med. 2018;7(7):3213–25.

    Article  CAS  PubMed Central  Google Scholar 

  249. Cacheux W, Dangles-Marie V, Rouleau E, Lazartigues J, Girard E, Briaux A, et al. Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma. Oncotarget. 2018;9(1):464–76.

    Article  PubMed  Google Scholar 

  250. Rogers JE, Jácome AAA, Ohinata A, Wolff R, Morris VK, Johnson B, et al. Outcomes with anti-EGFR monoclonal antibodies in metastatic and recurrent anal squamous cell carcinoma. Expert Rev Anticancer Ther. 2020;20(10):901–8.

    Article  CAS  PubMed  Google Scholar 

  251. Rogers JE, Ohinata A, Silva NN, Mehdizadeh A, Eng C. Epidermal growth factor receptor inhibition in metastatic anal cancer. Anticancer Drugs. 2016;27(8):804–8.

    Article  CAS  PubMed  Google Scholar 

  252. Wessely A, Heppt MV, Kammerbauer C, Steeb T, Kirchner T, Flaig MJ, et al. Evaluation of PD-L1 expression and HPV genotyping in anal squamous cell carcinoma. Cancers (Basel). 2020;12(9):2516.

    Article  CAS  Google Scholar 

  253. Govindarajan R, Gujja S, Siegel ER, Batra A, Saeed A, Lai K, et al. Programmed cell death-ligand 1 (PD-L1) expression in anal cancer. Am J Clin Oncol. 2018;41(7):638–42.

    Article  CAS  PubMed  Google Scholar 

  254. Zhao YJ, Sun WP, Peng JH, Deng YX, Fang YJ, Huang J, et al. Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients. Cancer Manag Res. 2018;10:1–11.

    Article  PubMed  Google Scholar 

  255. Ott PA, Piha-Paul SA, Munster P, Pishvaian MJ, van Brummelen EMJ, Cohen RB, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Cabel L, Jeannot E, Bieche I, Vacher S, Callens C, Bazire L, et al. Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma. Clin Cancer Res. 2018;24(22):5767–71.

    Article  CAS  PubMed  Google Scholar 

  257. Bernard-Tessier A, Jeannot E, Guenat D, Debernardi A, Michel M, Proudhon C, et al. Clinical validity of HPV circulating tumor DNA in advanced anal carcinoma: an ancillary study to the epitopes-HPV02 trial. Clin Cancer Res. 2019;25(7):2109–15.

    Article  CAS  PubMed  Google Scholar 

  258. Lee JY, Cutts RJ, White I, Augustin Y, Garcia-Murillas I, Fenwick K, et al. Next generation sequencing assay for detection of circulating HPV DNA (cHPV-DNA) in patients undergoing radical (chemo)radiotherapy in anal squamous cell carcinoma (ASCC). Front Oncol. 2020;10:505.

    Article  PubMed  PubMed Central  Google Scholar 

  259. Cabel L, Bidard FC, Servois V, Cacheux W, Mariani P, Romano E, et al. HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: a case report. Int J Cancer. 2017;141(8):1667–70.

    Article  CAS  PubMed  Google Scholar 

  260. Shia J. Anal adenocarcinoma. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 208–11.

    Google Scholar 

  261. Voltaggio L, McCluggage WG, Iding JS, Martin B, Longacre TA, Ronnett BM. A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas. Mod Pathol. 2020;33(5):944–52.

    Article  CAS  PubMed  Google Scholar 

  262. Katerji R, Liao X, Huber A, Zhang D. An unusual case of human papillomavirus-related anorectal adenocarcinoma with progression to perianal Paget’s disease. Int J Surg Pathol. 2020;2010:1066896920982367.

    Google Scholar 

  263. Lisovsky M, Patel K, Cymes K, Chase D, Bhuiya T, Morgenstern N. Immunophenotypic characterization of anal gland carcinoma: loss of p63 and cytokeratin 5/6. Arch Pathol Lab Med. 2007;131(8):1304–11.

    Article  PubMed  Google Scholar 

  264. Kuroda N, Tanida N, Ohara M, Hirouchi T, Mizuno K, Kubo A, et al. Anal canal adenocarcinoma with MUC5AC expression suggestive of anal gland origin. Med Mol Morphol. 2007;40(1):50–3.

    Article  PubMed  Google Scholar 

  265. Nishigami T, Kataoka TR, Ikeuchi H, Torii I, Sato A, Tomita N, et al. Adenocarcinomas associated with perianal fistulae in Crohn’s disease have a rectal, not an anal, immunophenotype. Pathology. 2011;43(1):36–9.

    Article  PubMed  Google Scholar 

  266. Goldblum JR, Hart WR. Perianal Paget’s disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol. 1998;22(2):170–9.

    Article  CAS  PubMed  Google Scholar 

  267. Herfs M, Roncarati P, Koopmansch B, Peulen O, Bruyere D, Lebeau A, et al. A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine. Br J Cancer. 2018;118(10):1302–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Klimstra DS, Klöppel G, La Rosa S, Rindi G. Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 16–9.

    Google Scholar 

  269. Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M, Grossman AB. Molecular pathology of well-differentiated gastro-entero-pancreatic neuroendocrine tumors. Endocr Pathol. 2021;32(1):169–91.

    Article  PubMed  Google Scholar 

  270. Soga J, Tazawa K. Pathologic analysis of carcinoids. Histologic reevaluation of 62 cases. Cancer. 1971;28(4):990–8.

    Article  CAS  PubMed  Google Scholar 

  271. McHugh KE, Mukhopadhyay S, Doxtader EE, Lanigan C, Allende DS. INSM1 is a highly specific marker of neuroendocrine differentiation in primary neoplasms of the gastrointestinal tract, appendix, and pancreas. Am J Clin Pathol. 2020;153(6):811–20.

    Article  CAS  PubMed  Google Scholar 

  272. Chen SF, Kasajima A, Yazdani S, Chan MS, Wang L, He YY, et al. Clinicopathologic significance of immunostaining of α-thalassemia/mental retardation syndrome X-linked protein and death domain-associated protein in neuroendocrine tumors. Hum Pathol. 2013;44(10):2199–203.

    Article  CAS  PubMed  Google Scholar 

  273. Egashira A, Morita M, Kumagai R, Taguchi KI, Ueda M, Yamaguchi S, et al. Neuroendocrine carcinoma of the esophagus: clinicopathological and immunohistochemical features of 14 cases. PLoS One. 2017;12(3):e0173501.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  274. Fujimasa K, Ohike N, Norose T, Isobe T, Kikuchi K, Otsuka K, et al. Frequent and specific involvement of changes of the p16-RB pathway in esophageal neuroendocrine carcinoma. Anticancer Res. 2019;39(4):1927–34.

    Article  CAS  PubMed  Google Scholar 

  275. Ishida H, Kasajima A, Kamei T, Miura T, Oka N, Yazdani S, et al. SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis. Mod Pathol. 2017;30(5):660–71.

    Article  CAS  PubMed  Google Scholar 

  276. Makuuchi R, Terashima M, Kusuhara M, Nakajima T, Serizawa M, Hatakeyama K, et al. Comprehensive analysis of gene mutation and expression profiles in neuroendocrine carcinomas of the stomach. Biomed Res. 2017;38(1):19–27.

    Article  CAS  PubMed  Google Scholar 

  277. Rindi G, Paolotti D, Fiocca R, Wiedenmann B, Henry JP, Solcia E. Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors. Virchows Arch. 2000;436(3):217–23.

    Article  CAS  PubMed  Google Scholar 

  278. Uccella S, Cerutti R, Vigetti D, Furlan D, Oldrini R, Carnevali I, et al. Histidine decarboxylase, DOPA decarboxylase, and vesicular monoamine transporter 2 expression in neuroendocrine tumors: immunohistochemical study and gene expression analysis. J Histochem Cytochem. 2006;54(8):863–75.

    Article  CAS  PubMed  Google Scholar 

  279. La Rosa S, Rindi G, Solcia E, Tang LH. Gastric neuroendocrine neoplasms. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 104–9.

    Google Scholar 

  280. Jakobsen AM, Andersson P, Saglik G, Andersson E, Kölby L, Erickson JD, et al. Differential expression of vesicular monoamine transporter (VMAT) 1 and 2 in gastrointestinal endocrine tumours. J Pathol. 2001;195(4):463–72.

    Article  CAS  PubMed  Google Scholar 

  281. Uccella S, La Rosa S, Volante M, Papotti M. Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol. 2018;29(2):150–68.

    Article  PubMed  Google Scholar 

  282. Srivastava A, Hornick JL. Immunohistochemical staining for CDX-2, PDX-1, NESP-55, and TTF-1 can help distinguish gastrointestinal carcinoid tumors from pancreatic endocrine and pulmonary carcinoid tumors. Am J Surg Pathol. 2009;33(4):626–32.

    Article  PubMed  Google Scholar 

  283. Gonzalez RS. Diagnosis and management of gastrointestinal neuroendocrine neoplasms. Surg Pathol Clin. 2020;13(3):377–97.

    Article  PubMed  Google Scholar 

  284. Bellizzi AM. SATB2 in neuroendocrine neoplasms: strong expression is restricted to well-differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas. Histopathology. 2020;76(2):251–64.

    Article  PubMed  Google Scholar 

  285. Khan MS, Luong TV, Watkins J, Toumpanakis C, Caplin ME, Meyer T. A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. Br J Cancer. 2013;108(9):1838–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, et al. Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies. Mod Pathol. 2015;28(5):686–94.

    Article  PubMed  Google Scholar 

  287. Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J, et al. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumor. Clin Cancer Res. 2016;22(1):250–8.

    Article  CAS  PubMed  Google Scholar 

  288. Andersson E, Arvidsson Y, Swärd C, Hofving T, Wängberg B, Kristiansson E, et al. Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets. Mod Pathol. 2016;29(6):616–29.

    Article  CAS  PubMed  Google Scholar 

  289. Yao J, Garg A, Chen D, Capdevila J, Engstrom P, Pommier R, et al. Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials. Endocr Relat Cancer. 2019;26(4):391–403.

    Article  CAS  PubMed  Google Scholar 

  290. Simbolo M, Vicentini C, Mafficini A, Fassan M, Pedron S, Corbo V, et al. Mutational and copy number asset of primary sporadic neuroendocrine tumors of the small intestine. Virchows Arch. 2018;473(6):709–17.

    Article  PubMed  PubMed Central  Google Scholar 

  291. Perren A, Basturk O, Bellizzi AM, Scoazec JY, Sipos B. Small intestinal and ampullary neuroendocrine neoplasms. In: WHO Classification of tumours Editorial board, editor. WHO classification of tumours. Digestive system tumours. 5th ed. Lyon, France: IARC Press; 2019. p. 131–4.

    Google Scholar 

  292. Idrees K, Padmanabhan C, Liu E, Guo Y, Gonzalez RS, Berlin J, et al. Frequent BRAF mutations suggest a novel oncogenic driver in colonic neuroendocrine carcinoma. J Surg Oncol. 2018;117(2):284–9.

    Article  CAS  PubMed  Google Scholar 

  293. Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E, et al. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer. 2015;22(1):35–45.

    Article  CAS  PubMed  Google Scholar 

  294. Pellat A, Dreyer C, Couffignal C, Walter T, Lombard-Bohas C, Niccoli P, et al. Clinical and biomarker evaluations of Sunitinib in patients with grade 3 digestive neuroendocrine neoplasms. Neuroendocrinology. 2018;107(1):24–31.

    Article  CAS  PubMed  Google Scholar 

  295. Roberts JA, Gonzalez RS, Das S, Berlin J, Shi C. Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy. Hum Pathol. 2017;70:49–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Öberg K, Califano A, Strosberg JR, Ma S, Pape U, Bodei L, et al. A meta-analysis of the accuracy of a neuroendocrine tumor mRNA genomic biomarker (NETest) in blood. Ann Oncol. 2020;31(2):202–12.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Health Sciences, Dokuz Eylul University, Izmir, Turkey

    Burcin Pehlivanoglu & S. Mehtat Unlu

  2. Department of Pathology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey

    Burcin Pehlivanoglu & S. Mehtat Unlu

Authors
  1. Burcin Pehlivanoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Mehtat Unlu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Burcin Pehlivanoglu .

Editor information

Editors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Health Sciences, Dokuz Eylul University, Ä°zmir, Turkey

    Sulen Sarioglu

  2. Department of Molecular Pathology, Graduate School of Health Sciences, Dokuz Eylul University, Ä°zmir, Turkey

    Ozgul Sagol

  3. Department of Molecular Pathology, Graduate School of Health Sciences, Dokuz Eylul University, Ä°zmir, Turkey

    Anil Aysal

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Pehlivanoglu, B., Unlu, S.M. (2022). Biomarkers in Gastrointestinal System Carcinomas. In: Sarioglu, S., Sagol, O., Aysal, A. (eds) Biomarkers in Carcinoma of Unknown Primary. Springer, Cham. https://doi.org/10.1007/978-3-030-84432-5_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-84432-5_7

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-84431-8

  • Online ISBN: 978-3-030-84432-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation