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Study of histopathologic parameters to define the prognosis of stage II colon cancer

  • Adriana Romiti
  • Michela RobertoEmail author
  • Paolo Marchetti
  • Arcangelo Di Cerbo
  • Rosa Falcone
  • Giorgia Campisi
  • Mario Ferri
  • Genoveffa Balducci
  • Giovanni Ramacciato
  • Luigi Ruco
  • Emanuela Pilozzi
Original Article
  • 79 Downloads

Abstract

Purpose

Stage II colon cancer (CC) represents a challenging scenario for the choice of adjuvant chemotherapy; here, histologic factors need to be weighed up to establish the risk of recurrence. Tumor budding (TB) has recently been indicated as a confident predictor of clinical outcome in CC. Likewise, the presence of poorly differentiated clusters (PDCs) in a tumor has been pointed out as a leading criterion of a tumor grading system. Our aim was to evaluate in patients with stage II CC the relationship between these features and clinical outcome.

Patients and methods

The study included 174 cases of stage II CC; histopathologic parameters such as TB, PDCs, microsatellite instability (MSI), and CDX2 expression were analyzed.

Results

There were 107 (70.9%), 32 (21.2%), and 12 (7.9%) TB scored 1, 2, and 3 respectively; 113 (72.9%), 30 (19.4%), and 12 (7.7%) tumors showed grade 1, 2, and 3 PDCs respectively. A high-MSI was detected in 32 cases (18.4%) while CDX2 was negative in 20 (11.5%) tumor samples. In the whole study population, only the TB was found to be associated with disease-specific survival (P = 0.01). No parameter apart from age (P = 0.04) was a significant prognostic factor for overall survival (P < 0.05). Other commonly reported variables, including tumor size, degree of tumor differentiation, lymphovascular invasion, number of lymph nodes harvested ≥ 12, MSI, and PDCs, were not shown to have significant results.

Conclusions

Although confirmatory studies are awaited, our work supports the role of the TB in defining risk groups of the stage II CC.

Keywords

Colon cancer Stage II Tumor budding Poorly differentiated cluster CDX2 Microsatellite instability 

Notes

Acknowledgments

We wished to thank Dr. Laura Di Fede and Dr. Denise Quacquarini for technical assistance with immunohistochemistry and molecular analysis.

Compliance with ethical standards

The study was conducted in accordance with the Declaration of Helsinki and the protocol approved by the institutional (Sapienza University) ethical committee (N.3874_2015/22.10.2015).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

384_2019_3279_MOESM1_ESM.docx (98 kb)
ESM 1 (DOCX 98.3 kb)

References

  1. 1.
    Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ (2007) QUASAR adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 370(9604):2020–2029CrossRefGoogle Scholar
  2. 2.
    Benson AB, Robert CH, Venook AP, Cederquist L, Chan E, V.-I. Cancer Center Yi-Jen Chen, H.S. Cooper, A. Fichera, J.L. Grem, P. Buffett Cancer Center, A. Grothey, H.S. Hochster, S. Hunt, A. Kamel, S. Krishnamurthi, M.F. Mulcahy, J.D. Murphy, S. Nurkin, L. Saltz, D. Shibata, J.M. Skibber, C.T. Sofocleous, E.M. Stoffel, E. Stotsky-Himelfarb, C.G. Willett, C.S. Wu, N. Deborah Freedman-Cass, K.M. Gregory (2017) NCCN Guidelines Version 2.2017 Panel Members Colon Cancer MD/Vice-Chair UCSF Helen Diller Family Comprehensive Cancer CenterGoogle Scholar
  3. 3.
    Labianca R, Nordlinger B, Beretta GD, Mosconi S, Mandala M, Cervantes A, Arnold D (2013) Early colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 24(suppl 6):vi64–vi72CrossRefGoogle Scholar
  4. 4.
    Hutchins G, Southward K, Handley K, Magill L, Beaumont C, Stahlschmidt J, Richman S, Chambers P, Seymour M, Kerr D, Gray R, Quirke P (2011) Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 29(10):1261–1270CrossRefGoogle Scholar
  5. 5.
    Thomas GD, Dixon MF, Smeeton NC, Williams NS (1983) Observer variation in the histological grading of rectal carcinoma. J Clin Pathol 36(4):385–391CrossRefGoogle Scholar
  6. 6.
    Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC (2002) Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 40:127–132CrossRefGoogle Scholar
  7. 7.
    Ueno H, Mochizuki H, Hashiguchi Y, Shimazaki H, Aida S, Hase K, Matsukuma S, Kanai T, Kurihara H, Ozawa K, Yoshimura K, Bekku S (2004) Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology. 127:385–394CrossRefGoogle Scholar
  8. 8.
    Ueno H, Kajiwara Y, Shimazaki H, Shinto E, Hashiguchi Y, Nakanishi K, Maekawa K, Katsurada Y, Nakamura T, Mochizuki H, Yamamoto J, Hase K (2012) New criteria for histologic grading of colorectal cancer. Am J Surg Pathol 36:193–201CrossRefGoogle Scholar
  9. 9.
    Klingbiel D, Saridaki Z, Roth AD, Bosman FT, Delorenzi M, Tejpar S (2015) Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial. Ann Oncol 26(1):126–132CrossRefGoogle Scholar
  10. 10.
    Bertagnolli MM, Redston M, Compton CC, Niedzwiecki D, Mayer RJ, Goldberg RM, Colacchio TA, Saltz LB, Warren RS (2011) Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer—a study of CALGB 9581 and 89803. J Clin Oncol 29(23):3153–3162CrossRefGoogle Scholar
  11. 11.
    Romiti A, Rulli E, Pilozzi E, Gerardi C, Roberto M, Legramandi L, Falcone R, Pacchetti I, Marchetti P, Floriani I (2016) Exploring the prognostic role of microsatellite instability in patients with stage II colorectal cancer: a systematic review and meta-analysis. Clin Colorectal CancerGoogle Scholar
  12. 12.
    Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgó E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF (2016) CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 374(3):211–222CrossRefGoogle Scholar
  13. 13.
    Pilati C, Taieb J, Balogoun R, Marisa L, de Reyniès A, Laurent-Puig P (2017) CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification. Ann Oncol 28(5):1032–1035CrossRefGoogle Scholar
  14. 14.
    Tomasello G, Barni, S, Turati L, Ghidini M, Pezzica E, Passalacqua R, Petrelli F (2018) Association of CDX2 expression with survival in early colorectal cancer: a systematic review and meta-analysisGoogle Scholar
  15. 15.
    Lugli A, Kirsch R, Ajioka Y, Bosman F, Cathomas G, Dawson H, El Zimaity H, Fléjou JF, Hansen TP, Hartmann A, Kakar S, Langner C, Nagtegaal I, Puppa G, Riddell R, Ristimäki A, Sheahan K, Smyrk T, Sugihara K, Terris B, Ueno H, Vieth M, Zlobec I, Quirke P (2017) Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 30:1299–1311CrossRefGoogle Scholar
  16. 16.
    Betge J, Kornprat P, Pollheimer MJ, Lindtner RA, Schlemmer A, Rehak P, Vieth M, Langner C (2012) Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer. Ann Surg Oncol 19(12):3706–3712CrossRefGoogle Scholar
  17. 17.
    Kinoshita O, Kishimoto M, Murayama Y, Yasukawa S, Konishi E, Otsuji E, Yanagisawa A (2015) Poorly differentiated clusters with larger extents have a greater impact on survival: a semi-quantitative pathological evaluation for 239 patients with non-mucinous pT2-3 colorectal carcinoma. World J Surg Oncol 13:140CrossRefGoogle Scholar
  18. 18.
    Kinoshita O, Kishimoto M, Murayama Y, Kuriu Y, Nakanishi M, Sakakura C, Otsuji E, Yanagisawa A (2016) The number of metastatic lymph nodes exhibiting poorly differentiated clusters predicts survival in patients with pStage III colorectal cancer. Int J Color Dis 31:283–290CrossRefGoogle Scholar
  19. 19.
    Pilozzi E, Maresca C, Duranti E, Giustiniani MC, Catalanotto C, Lucarelli M, Cogoni C, Ferri M, Ruco L, Zardo G (2015) Left-sided early-onset vs late-onset colorectal carcinoma: histologic, clinical, and molecular differences. Am J Clin Pathol 143(3):374–384CrossRefGoogle Scholar
  20. 20.
    Punt CJA, Buyse M, Kohne C-H, Hohenberger P, Labianca R, Schmoll HJ, Pahlman L, Sobrero A, Douillard J-Y (2007) Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. JNCI J Natl Cancer Inst 99(13):998–1003CrossRefGoogle Scholar
  21. 21.
    Gray RG, Quirke P, Handley K, Lopatin M, Magill L, Baehner FL, Beaumont C, Clark-Langone KM, Yoshizawa CN, Lee M, Watson D, Shak S, Kerr DJ (2011) Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. J Clin Oncol 29(35):4611–4619CrossRefGoogle Scholar
  22. 22.
    Merkel S, Wein K, Günther T, Papadopoulos, Hohenberger W, Hermanek P (2001) High-risk groups of patients with stage II colon carcinoma. Cancer. 92:1435–1443CrossRefGoogle Scholar
  23. 23.
    Morris M, Platell C, de Boer B, McCaul K, Iacopetta B (2006) Population-based study of prognostic factors in stage II colonic cancer. Br J Surg 93(7):866–871CrossRefGoogle Scholar
  24. 24.
    Compton CC, Fielding LP, Burgart LJ, Conley B, Cooper HS, Hamilton SR, Hammond ME, Henson DE, Hutter RV, Nagle RB, Nielsen ML, Sargent DJ, Taylor CR, Welton M, Willett C (2000) Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med 124(7):979–994Google Scholar
  25. 25.
    Rosty C, Williamson EJ, Clendenning M, Walters RJ, Win AK, Jenkins MA, Hopper JL, Winship IM, Southey MC, Giles GG, English DR, Buchanan DD (2014) Should the grading of colorectal adenocarcinoma include microsatellite instability status? Hum Pathol 45(10):2077–2084CrossRefGoogle Scholar
  26. 26.
    Tanaka M, Hashiguchi Y, Ueno H, Hase K, Mochizuki H (2003) Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum 46:1054–1059CrossRefGoogle Scholar
  27. 27.
    De Smedt L, Palmans S, Sagaert X (2016) Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch 468(4):397–408CrossRefGoogle Scholar
  28. 28.
    Ueno H, Hashiguchi Y, Kajiwara Y, Shinto E, Shimazaki H, Kurihara H, Mochizuki H, Hase K (2010) Proposed objective criteria for “grade 3” in early invasive colorectal cancer. Am J Clin Pathol 134(2):312–322CrossRefGoogle Scholar
  29. 29.
    Barresi V, Reggiani Bonetti L, Ieni A, Caruso RA, Tuccari G (2017) Poorly differentiated clusters: clinical impact in colorectal cancer. Clin Colorectal Cancer 16(1):9–15CrossRefGoogle Scholar
  30. 30.
    Ueno H, Konishi T, Ishikawa Y, Shimazaki H, Ueno M, Aosasa S, Saiura A, Hase K, Yamamoto J (2014) Histologic categorization of fibrotic cancer stroma in the primary tumor is an independent prognostic index in resectable colorectal liver metastasis. Am J Surg Pathol 38(10):1380–1386CrossRefGoogle Scholar
  31. 31.
    van Wyk HC, Park J, Roxburgh C, Horgan P, Foulis A, McMillan DC (2015) The role of tumour budding in predicting survival in patients with primary operable colorectal cancer: a systematic reviewGoogle Scholar
  32. 32.
    Wang LM, Kevans D, Mulcahy H, O’Sullivan J, Fennelly D, Hyland J, O’Donoghue D, Sheahan K (2009) Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol 33:134–141CrossRefGoogle Scholar
  33. 33.
    Lee VWK, Chan KF (2018) Tumor budding and poorly-differentiated cluster in prognostication in stage II colon cancer. Pathol Res Pract 214(3):402–407CrossRefGoogle Scholar
  34. 34.
    Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, Hamilton SR, Laurent-Puig P, Gryfe R, Shepherd LE, Tu D, Redston M, Gallinger S (2003) Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349(3):247–257CrossRefGoogle Scholar
  35. 35.
    Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, Yothers G, Allegra C, Moore MJ, Gallinger S, Sargent DJ (2011) DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 103(11):863–875CrossRefGoogle Scholar
  36. 36.
    Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz J-F, Sinicrope F, Gallinger S (2010) Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 28(20):3219–3226CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Adriana Romiti
    • 1
  • Michela Roberto
    • 1
    • 2
    Email author
  • Paolo Marchetti
    • 1
  • Arcangelo Di Cerbo
    • 1
  • Rosa Falcone
    • 1
  • Giorgia Campisi
    • 1
  • Mario Ferri
    • 2
  • Genoveffa Balducci
    • 2
  • Giovanni Ramacciato
    • 2
  • Luigi Ruco
    • 1
  • Emanuela Pilozzi
    • 1
  1. 1.Department of Clinical and Molecular Medicine, Sant’Andrea HospitalUniversity “La Sapienza”RomeItaly
  2. 2.Department of Medical-Surgical Sciences and Translation MedicineSant’Andrea Hospital, University “La Sapienza”RomeItaly

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