Signet ring cell component in pretreatment biopsy predicts pathological response to preoperative chemoradiotherapy in rectal cancer

Abstract

Purpose

Neoadjuvant therapy is routinely used in the management of locally advanced rectal cancer. This study aimed to evaluate the predictive value of pathological parameters in tumor response after treatment.

Methods

We reviewed the hematoxylin–eosin slides from pretreatment biopsies of 150 rectal cancer patients who received preoperative chemoradiotherapy (PCRT) at Sun Yat-sen University Cancer Center between May 2013 and June 2016. Pathological and clinical parameters were both studied. The tumor response after chemoradiotherapy was evaluated using the tumor regression grade (TRG). Logistic regression was used to evaluate the relevance between these parameters and tumor response.

Results

Complete tumor response (TRG0 and pCR) to PCRT was identified in 40 (26.7%) patients. The pCR rate was 93.33% (14 of 15) in cases with signet ring cell component versus 19.26% (26 of 135) in those without signet ring cell component (p < 0.001). Four cases with signet ring cell component were evaluated as clinical complete response (cCR), all of whom also achieved pCR; in contrast, only 9 of 15 (60%) cCR cases without signet ring cell achieved pCR.

Conclusion

Our data suggest that the signet ring cell component in pretreatment biopsies may be a potential predictor of tumor response to PCRT in rectal cancer. This suggests patients with clinical complete response are more suitable for a wait-and-watch approach.

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Fig. 1
Fig. 2

Data Availability

The authenticity of this article has been validated by uploading the key raw data onto the Research Data Deposit public platform (www.researchdata.org.cn), with the approval RDD number as RDDA2020001420.

Abbreviations

PCRT:

Preoperative chemoradiotherapy

TRG:

Tumor regression grade

pCR:

Pathological complete response

SRCC:

Signet ring cell cancer

PDCs:

Poorly differentiated clusters

CEA:

Carcinoembryonic antigen

CA-199:

Carbohydrate antigen-199

CT:

Computerized tomography

MRI:

Magnetic resonance imaging

References

  1. 1.

    Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. CA Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Weiser MR, Quah HM, Shia J et al (2009) Sphincter preservation in low rectal cancer is facilitated by preoperative chemoradiation and intersphincteric dissection. Ann Surg 249(2):236–242. https://doi.org/10.1097/SLA.0b013e318195e17c

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rodel C, Liersch T, Becker H et al (2012) Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13(7):679–687. https://doi.org/10.1016/S1470-2045(12)70187-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Sauer R, Liersch T, Merkel S et al (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30(16):1926–1933. https://doi.org/10.1200/JCO.2011.40.1836

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Quah HM, Chou JF, Gonen M et al (2008) Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer 113(1):57–64. https://doi.org/10.1002/cncr.23516

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rodel C, Martus P, Papadoupolos T et al (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23(34):8688–8696. https://doi.org/10.1200/JCO.2005.02.1329

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Lee YC, Hsieh CC, Chuang JP (2013) Prognostic significance of partial tumor regression after preoperative chemoradiotherapy for rectal cancer: a meta-analysis. Dis Colon Rectum 56(9):1093–1101. https://doi.org/10.1097/DCR.0b013e318298e36b

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hartley A, Ho KF, McConkey C et al (2005) Pathological complete response following pre-operative chemoradiotherapy in rectal cancer: analysis of phase II/III trials. Br J Radiol 78(934):934–938. https://doi.org/10.1259/bjr/86650067

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Martin ST, Heneghan HM, Winter DC (2012) Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer. Br J Surg 99(7):918–928. https://doi.org/10.1002/bjs.8702

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Maas M, Nelemans PJ, Valentini V et al (2010) Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 11(9):835–844. https://doi.org/10.1016/S1470-2045(10)70172-8

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Renehan AG, Malcomson L, Emsley R et al (2016) Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol 17(2):174–183. https://doi.org/10.1016/S1470-2045(15)00467-2

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hyngstrom JR, Hu CY, Xing Y et al (2012) Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol 19(9):2814–2821. https://doi.org/10.1245/s10434-012-2321-7

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Fu J, Wu L, Jiang M et al (2016) Signet ring cell carcinoma of resectable metastatic colorectal cancer has rare surgical value. J Surg Oncol 114(8):1004–1008. https://doi.org/10.1002/jso.24437

    CAS  Article  Google Scholar 

  14. 14.

    Bosman FT, World Health Organization, International Agency for Research on Cancer (2010) WHO classification of tumours of the digestive system. World Health Organization classification of tumours, vol 3, 4th edn. International Agency for Research on Cancer, Lyon

  15. 15.

    Yun SO, Cho YB, Lee WY et al (2017) Clinical significance of signet-ring-cell colorectal cancer as a prognostic factor. Ann Coloproctol 33(6):232–238. https://doi.org/10.3393/ac.2017.33.6.232

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Hugen N, Verhoeven RH, Lemmens VE et al (2015) Colorectal signet-ring cell carcinoma: benefit from adjuvant chemotherapy but a poor prognostic factor. Int J Cancer 136(2):333–339. https://doi.org/10.1002/ijc.28981

    CAS  Article  Google Scholar 

  17. 17.

    Wu SG, Zhang WW, Sun JY et al (2017) Preoperative radiotherapy improves survival in rectal signet-ring cell carcinoma-a population-based study. Radiat Oncol 12(1):141. https://doi.org/10.1186/s13014-017-0874-0

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Rombouts AJM, Hugen N, Verhoeven RHA et al (2018) Tumor response after long interval comparing 5×5Gy radiation therapy with chemoradiation therapy in rectal cancer patients. Eur J Surg Oncol 44(7):1018–1024. https://doi.org/10.1016/j.ejso.2018.03.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Jayanand SB, Seshadri RA, Tapkire R (2011) Signet ring cell histology and non-circumferential tumors predict pathological complete response following neoadjuvant chemoradiation in rectal cancers. Int J Colorectal Dis 26(1):23–27. https://doi.org/10.1007/s00384-010-1082-7

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Lugli A, Kirsch R, Ajioka Y et al (2017) Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol 30(9):1299–1311. https://doi.org/10.1038/modpathol.2017.46

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Rogers AC, Gibbons D, Hanly AM et al (2014) Prognostic significance of tumor budding in rectal cancer biopsies before neoadjuvant therapy. Mod Pathol 27(1):156–162. https://doi.org/10.1038/modpathol.2013.124

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Reggiani Bonetti L, Lionti S, Domati F et al (2017) Histological grading based on poorly differentiated clusters is predictive of tumour response and clinical outcome in rectal carcinoma treated with neoadjuvant chemoradiotherapy. Histopathology 71(3):393–405. https://doi.org/10.1111/his.13242

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Orsini RG, Verhoeven RH, Lemmens VE et al (2015) Comparable survival for young rectal cancer patients, despite unfavourable morphology and more advanced-stage disease. Eur J Cancer 51(13):1675–1682. https://doi.org/10.1016/j.ejca.2015.06.005

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ling CR, Wang R, Wang MJ et al (2017) Prognosis and value of preoperative radiotherapy in locally advanced rectal signet-ring cell carcinoma. Sci Rep 7:45334. https://doi.org/10.1038/srep45334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Appelt AL, Ploen J, Harling H et al (2015) High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol 16(8):919–927. https://doi.org/10.1016/S1470-2045(15)00120-5

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Chadi SA, Malcomson L, Ensor J et al (2018) Factors affecting local regrowth after watch and wait for patients with a clinical complete response following chemoradiotherapy in rectal cancer (InterCoRe consortium): an individual participant data meta-analysis. Lancet Gastroenterol Hepatol 3(12):825–836. https://doi.org/10.1016/S2468-1253(18)30301-7

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Smith JJ, Chow OS, Gollub MJ et al (2015) Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer 15:767. https://doi.org/10.1186/s12885-015-1632-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Dossa F, Chesney TR, Acuna SA et al (2017) A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2(7):501–513. https://doi.org/10.1016/S2468-1253(17)30074-2

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Deng Y, Chi P, Lan P et al (2016) Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol 34(27):3300–3307. https://doi.org/10.1200/JCO.2016.66.6198

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hugen N, Brown G, Glynne-Jones R et al (2016) Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol 13(6):361–369. https://doi.org/10.1038/nrclinonc.2015.140

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Sung CO, Seo JW, Kim KM et al (2008) Clinical significance of signet-ring cells in colorectal mucinous adenocarcinoma. Mod Pathol 21(12):1533–1541. https://doi.org/10.1038/modpathol.2008.170

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Chen JS, Hsieh PS, Hung SY et al (2004) Clinical significance of signet ring cell rectal carcinoma. Int J Colorectal Dis 19(2):102–107. https://doi.org/10.1007/s00384-003-0515-y

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Pande R, Sunga A, Levea C et al (2008) Significance of signet-ring cells in patients with colorectal cancer. Dis Colon Rectum 51(1):50–55. https://doi.org/10.1007/s10350-007-9073-7

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sasaki S, Masaki T, Umetani N et al (1998) Characteristics in primary signet-ring cell carcinoma of the colorectum, from clinicopathological observations. Jpn J Clin Oncol 28(3):202–206

    CAS  Article  Google Scholar 

  35. 35.

    Nam JY, Oh BY, Hong HK et al (2018) Molecular characterization of colorectal signet-ring cell carcinoma using whole-exome and RNA sequencing. Transl Oncol 11(4):836–844. https://doi.org/10.1016/j.tranon.2018.04.007

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Findlay VJ, Wang C, Nogueira LM et al (2014) SNAI2 modulates colorectal cancer 5-fluorouracil sensitivity through miR145 repression. Mol Cancer Ther 13(11):2713–2726. https://doi.org/10.1158/1535-7163.MCT-14-0207

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kawabata Y, Tomita N, Monden T et al (1999) Molecular characteristics of poorly differentiated adenocarcinoma and signet-ring-cell carcinoma of colorectum. Int J Cancer 84(1):33–38

    CAS  Article  Google Scholar 

  38. 38.

    Backes Y, Elias SG, Groen JN et al (2018) Histologic Factors Associated With Need for Surgery in Patients With Pedunculated T1 Colorectal Carcinomas. Gastroenterology 154(6):1647–1659. https://doi.org/10.1053/j.gastro.2018.01.023

    Article  Google Scholar 

  39. 39.

    Zlobec I, Lugli A (2018) Tumour budding in colorectal cancer: molecular rationale for clinical translation. Nat Rev Cancer 18(4):203–204. https://doi.org/10.1038/nrc.2018.1

    CAS  Article  Google Scholar 

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Acknowledgements

We thank all the patients who participated in this study and for their willingness to contribute valuable data for this manuscript.

Funding

This work was supported by grants from the Natural Science Foundation of China (81802942).

Author information

Affiliations

Authors

Contributions

Conception and design: JPY; administrative support: HZZ; provision of study materials or patients: SXL, YHH, PRD; collection and assembly of data: XC, ZXW, SBZ; data analysis and interpretation: XC, ZXW; manuscript writing: all authors; final approval of manuscript: all authors.

Corresponding authors

Correspondence to Huizhong Zhang or Jingping Yun.

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Conflict of interest

There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Ethical approval

The study was approved by the ethics committee of the Sun Yat-sen University Cancer Center.

Informed consent

All patients were systemically asked consent to the use of anonymous data for analysis and publication.

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Supplemental Fig. 1

(A) shows the intral-tumor tumor budding. (B) shows the poorly differentiated clusters. Supplementary material 1 (TIFF 1524 kb)

Supplemental Fig. 2

The disease-free survival curve of signet ring cell (SRC) and non-SRC group. Supplementary material 2 (TIFF 40 kb)

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Cite this article

Chao, X., Wang, Z., Lu, S. et al. Signet ring cell component in pretreatment biopsy predicts pathological response to preoperative chemoradiotherapy in rectal cancer. Int J Clin Oncol (2020). https://doi.org/10.1007/s10147-020-01697-8

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Keywords

  • Signet ring cell cancer
  • Preoperative chemoradiotherapy
  • Tumor response