Skip to main content

Is Preoperative Chemotherapy Followed by Surgery the Appropriate Treatment for Signet Ring Cell Containing Adenocarcinomas of the Esophagogastric Junction and Stomach?

Annals of Surgical Oncology volume 21, pages 1739–1748 (2014)Cite this article

Background

Recent data suggest primary resection as the preferable approach in patients with signet ring cell gastric cancer (SRC). The aim of our retrospective exploratory study was to evaluate the influence of SRC on prognosis and response in esophagogastric adenocarcinoma treated with neoadjuvant chemotherapy.

Methods

A total of 723 locally advanced esophagogastric adenocarcinomas (cT3/4 N any) documented in a prospective database from two academic centers were classified according to the WHO definition for SRC (more than 50 % SRC) and analyzed for their association with response and prognosis after neoadjuvant treatment.

Results

A total of 235 tumors (32.5 %) contained SRC. Median survival of SRC was 26.3 compared with 46.6 months (p < 0.001) for non-SRC. SRC were significantly associated with female gender, gastric localization, advanced ypT and R1/2 categories, and lower risk of surgical complications and anastomotic leakage (each p < 0.001). Clinical (21.1 vs. 33.7 %, p = 0.001) and histopathological response (less than 10 % residual tumor: 16.3 vs. 28.9 %, p < 0.001) were significantly less frequent in SRC. Clinical response (p = 0.003) and complete histopathological response (pCR) (3.4 %) (p = 0.003) were associated with improved prognosis in SRC. Clinical response, surgical complications, ypTN categories, but not SRC were independent prognostic factors in forward Cox regression analysis in R0 resected patients. Risk of peritoneal carcinomatosis was increased (p < 0.001), while local (p = 0.015) and distant metastases (p = 0.02) were less frequent than in non-SRC.

Conclusions

Prognosis of SRC is unfavorable. Although response to neoadjuvant chemotherapy is rare in SRC, it is associated with improved outcome. Thus, chemotherapy might not generally be abandoned in SRC. A stratification based on SRC should be included in clinical trials.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006;355:11–20.

    CAS  PubMed  Article  Google Scholar 

  2. Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29:1715–21.

    CAS  PubMed  Article  Google Scholar 

  3. Schuhmacher C, Gretschel S, Lordick F, Reichardt P, Hohenberger W, Eisenberger CF, et al. Neoadjuvant chemotherapy compared with surgery alone for locally advanced cancer of the stomach and cardia: European Organisation for Research and Treatment of Cancer randomized trial 40954. J Clin Oncol. 2010;28:5210–8.

    PubMed Central  PubMed  Article  Google Scholar 

  4. Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92.

    PubMed  Article  Google Scholar 

  5. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84.

    PubMed  Article  Google Scholar 

  6. Lowy AM, Mansfield PF, Leach SD, Pazdur R, Dumas P, Ajani JA. Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer. Ann Surg. 1999;229:303–8.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. Ott K, Fink U, Becker K, Stahl A, Dittler HJ, Busch R, et al. Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial. J Clin Oncol. 2003;21:4604–10.

    CAS  PubMed  Article  Google Scholar 

  8. Becker K, Reim D, Novotny A, Zum Büschenfelde CM, Engel J, et al. Proposal for a multifactorial prognostic score that accurately classifies 3 groups of gastric carcinoma patients with different outcomes after neoadjuvant chemotherapy and surgery. Ann Surg. 2012;256:1002–7.

    PubMed  Article  Google Scholar 

  9. Blank S, Blaker H, Schaible A, Lordick F, Grenacher L, Buechler M, et al. Impact of pretherapeutic routine clinical staging for the individualization of treatment in gastric cancer patients. Langenbecks Arch Surg. 2012;397:45–55.

    PubMed  Article  Google Scholar 

  10. Ott K, Rachakonda PS, Panzram B, Keller G, Lordick F, Becker K, et al. DNA repair gene and MTHFR gene polymorphisms as prognostic markers in locally advanced adenocarcinoma of the esophagus or stomach treated with cisplatin and 5-fluorouracil-based neoadjuvant chemotherapy. Ann Surg Oncol. 2011;18:2688–98.

    PubMed  Article  Google Scholar 

  11. Reim D, Gertler R, Novotny A, Becker K, zum Büschenfelde CM, Ebert M, et al. Adenocarcinomas of the esophagogastric junction are more likely to respond to preoperative chemotherapy than distal gastric cancer. Ann Surg Oncol. 2012;19:2108–18.

    PubMed  Article  Google Scholar 

  12. Wu H, Rusiecki JA, Zhu K, Potter J, Devesa SS. Stomach carcinoma incidence patterns in the United States by histologic type and anatomic site. Cancer Epidemiol Biomarkers Prev. 2009;18:1945–52.

    PubMed Central  PubMed  Article  Google Scholar 

  13. Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg. 2009;250:878–87.

    PubMed  Article  Google Scholar 

  14. Li C, Kim S, Lai JF, Hyung WJ, Choi WH, Choi SH, et al. Advanced gastric carcinoma with signet ring cell histology. Oncology. 2007;72:64–8.

    PubMed  Article  Google Scholar 

  15. Messager M, Lefevre JH, Pichot-Delahaye V, Souadka A, Piessen G, Mariette C. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg. 2011;254:684–93; discussion 693.

    PubMed  Article  Google Scholar 

  16. Rougier P, Mahjoubi M, Lasser P, Ducreux M, Oliveira J, Ychou M, et al. Neoadjuvant chemotherapy in locally advanced gastric carcinoma—a phase II trial with combined continuous intravenous 5-fluorouracil and bolus cisplatinum. Eur J Cancer. 1994;30A:1269–75.

    CAS  PubMed  Article  Google Scholar 

  17. Takiuchi H, Hirata I, Kawabe S, Egashira Y, Katsu K. Immunohistochemical expression of vascular endothelial growth factor can predict response to 5-fluorouracil and cisplatin in patients with gastric adenocarcinoma. Oncol Rep. 2000;7:841–6.

    CAS  PubMed  Google Scholar 

  18. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.

    CAS  PubMed  Google Scholar 

  19. Becker K, Langer R, Reim D, Novotny A, Meyer zum Buschenfelde C, Engel J, et al. Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases. Ann Surg. 2011;253:934–9.

    PubMed  Article  Google Scholar 

  20. Lorenzen S, Blank S, Lordick F, Siewert JR, Ott K. Prediction of response and prognosis by a score including only pretherapeutic parameters in 410 neoadjuvant treated gastric cancer patients. Ann Surg Oncol. 2012;19:2119–27.

    PubMed  Article  Google Scholar 

  21. Lorenzen S, Panzram B, Rosenberg R, Nekarda H, Becker K, Schenk U, et al. Prognostic significance of free peritoneal tumor cells in the peritoneal cavity before and after neoadjuvant chemotherapy in patients with gastric carcinoma undergoing potentially curative resection. Ann Surg Oncol. 2010;17:2733–9.

    PubMed  Article  Google Scholar 

  22. Ott K, Herrmann K, Schuster T, Langer R, Becker K, Wieder HA, et al. Molecular imaging of proliferation and glucose utilization: utility for monitoring response and prognosis after neoadjuvant therapy in locally advanced gastric cancer. Ann Surg Oncol. 2011;18:3316–23.

    PubMed  Article  Google Scholar 

  23. Ott K, Herrmann K, Lordick F, Wieder H, Weber WA, Becker K, et al. Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a prospective study. Clin Cancer Res. 2008;14:2012–8.

    CAS  PubMed  Article  Google Scholar 

  24. Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer. 2003;98:1521–30.

    PubMed  Article  Google Scholar 

  25. Bader FG, Lordick F, Fink U, Becker K, Hofler H, Busch R, et al. Paclitaxel in the neoadjuvant treatment for adeno carcinoma of the distal esophagus (AEG I). A comparison of two phase II trials with long-term follow-up. Onkologie. 2008;31:366–72.

    CAS  PubMed  Article  Google Scholar 

  26. Fink U, Schuhmacher C, Stein HJ, Busch R, Feussner H, Dittler HJ, et al. Preoperative chemotherapy for stage III–IV gastric carcinoma: feasibility, response and outcome after complete resection. Br J Surg. 1995;82:1248–52.

    CAS  PubMed  Article  Google Scholar 

  27. Schuhmacher CP, Fink U, Becker K, Busch R, Dittler HJ, Mueller J, et al. Neoadjuvant therapy for patients with locally advanced gastric carcinoma with etoposide, doxorubicin, and cisplatinum. Closing results after 5 years of follow-up. Cancer. 2001;91:918–27.

    CAS  PubMed  Article  Google Scholar 

  28. Siewert JR, Stein HJ, Feith M, Bruecher BL, Bartels H, Fink U. Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Ann Surg. 2001;234:360–7; discussion 368–9.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  29. Wang SY, Yeh CN, Lee HL, Liu YY, Chao TC, Hwang TL, et al. Clinical impact of positive surgical margin status on gastric cancer patients undergoing gastrectomy. Ann Surg Oncol. 2009;16:2738–43.

    PubMed  Article  Google Scholar 

  30. Chan DS, Reid TD, Howell I, Lewis WG. Systematic review and meta-analysis of the influence of circumferential resection margin involvement on survival in patients with operable oesophageal cancer. Br J Surg. 2013;100:456–64.

    CAS  PubMed  Article  Google Scholar 

  31. Raziee HR, Cardoso R, Seevaratnam R, Mahar A, Helyer L, Law C, et al. Systematic review of the predictors of positive margins in gastric cancer surgery and the effect on survival. Gastric Cancer. 2012;15 Suppl 1:S116–24.

    PubMed  Article  Google Scholar 

  32. Chirieac LR, Swisher SG, Correa AM, Ajani JA, Komaki RR, Rashid A, et al. Signet-ring cell or mucinous histology after preoperative chemoradiation and survival in patients with esophageal or esophagogastric junction adenocarcinoma. Clin Cancer Res. 2005;11:2229–36.

    CAS  PubMed  Article  Google Scholar 

  33. van Heijl M, van Lanschot JJ, Koppert LB, van Berge Henegouwen MI, Muller K, Steyerberg EW, et al. Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS). BMC Surg. 2008;8:21.

    PubMed Central  PubMed  Article  Google Scholar 

  34. Ott K, Blank S, Becker K, Langer R, Weichert W, Roth W, et al. Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10% residual tumor. Langenbecks Arch Surg. 2013;398:239–49.

    PubMed  Article  Google Scholar 

  35. Homann N, Pauligk C, Luley K, Werner Kraus T, Bruch HP, Atmaca A, et al. Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5-fluorouracil, oxaliplatin and docetaxel. Int J Cancer. 2012;130:1706–13.

    CAS  PubMed  Article  Google Scholar 

  36. Ajani JA, Correa AM, Walsh GL, Komaki R, Lee JH, Vaporciyan AA, et al. Trimodality therapy without a platinum compound for localized carcinoma of the esophagus and gastroesophageal junction. Cancer. 2010;116:1656–63.

    CAS  PubMed  Article  Google Scholar 

  37. Lordick F, Ott K, Weitz J, Jager D. The evolving role of catumaxomab in gastric cancer. Expert Opin Biol Ther. 2008;8:1407–15.

    CAS  PubMed  Article  Google Scholar 

  38. Sujendran V, Wheeler J, Baron R, Warren BF, Maynard N. Effect of neoadjuvant chemotherapy on circumferential margin positivity and its impact on prognosis in patients with resectable oesophageal cancer. Br J Surg. 2008;95:191–4.

    CAS  PubMed  Article  Google Scholar 

  39. Jass JR, Sobin LH, Watanabe H. The World Health Organization’s histologic classification of gastrointestinal tumors. A commentary on the second edition. Cancer. 1990;66:2162–7.

    CAS  PubMed  Article  Google Scholar 

  40. Piessen G, Amielh D, Messager M, Vinatier E, Leteurtre E, Triboulet JP, et al. Is pretreatment endoscopic biopsy a good predictor of signet ring cell histology in gastric carcinoma? World J Surg. 2012;36:346–54.

    PubMed  Article  Google Scholar 

  41. Flucke U, Monig SP, Baldus SE, Zirbes TK, Bollschweiler E, Thiele J, et al. Differences between biopsy- or specimen-related Lauren and World Health Organization classification in gastric cancer. World J Surg. 2002;26:137–40.

    PubMed  Article  Google Scholar 

  42. Dikken JL, Coit DG, Klimstra DS, Rizk NP, van Grieken N, Ilson D, et al. Prospective impact of tumor grade assessment in biopsies on tumor stage and prognostic grouping in gastroesophageal adenocarcinoma: relevance of the seventh edition American Joint Committee on Cancer Staging Manual revision. Cancer. 2012;118:349–57.

    PubMed  Article  Google Scholar 

  43. Schneider PM, Metzger R, Schaefer H, Baumgarten F, Vallbohmer D, Brabender J, et al. Response evaluation by endoscopy, rebiopsy, and endoscopic ultrasound does not accurately predict histopathologic regression after neoadjuvant chemoradiation for esophageal cancer. Ann Surg. 2008;248:902–8.

    PubMed  Article  Google Scholar 

Download references

Acknowledgment

We thank Catherine Bernaciak PhD for revising the manuscript.

Author information

Affiliations

  1. Department of Surgery, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany

    Ulrike Heger MD, Susanne Blank MD, Christiane Wiecha MS, Maria Burian MD, Markus Büchler MD & Katja Ott MD

  2. Department of Pathology, University of Bern, Bern, Switzerland

    Rupert Langer MD

  3. Department of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    Wilko Weichert MD

  4. University Cancer Center Leipzig (UCCL), University of Leipzig, Leipzig, Germany

    Florian Lordick MD

  5. Data Management, Institute of Medical Biometry and Statistics, IMBI, Heidelberg, Germany

    Thomas Bruckner PhD

  6. Department of Radiology, Technische Universitaet Muenchen, Munich, Germany

    Martin Dobritz MD

  7. Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg, Germany

    Christoph Springfeld MD, PhD

  8. Department of Diagnostic and Interventional Radiology, Heidelberg University Hospital, Heidelberg, Germany

    Lars Grenacher MD

  9. Directorate, University of Freiburg, Freiburg, Germany

    Jörg-Rüdiger Siewert MD

Authors
  1. Ulrike Heger MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susanne Blank MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christiane Wiecha MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rupert Langer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilko Weichert MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Florian Lordick MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas Bruckner PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Martin Dobritz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Burian MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christoph Springfeld MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lars Grenacher MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jörg-Rüdiger Siewert MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Markus Büchler MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Katja Ott MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katja Ott MD.

Additional information

Ulrike Heger and Susanne Blank contributed equally to this article.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Heger, U., Blank, S., Wiecha, C. et al. Is Preoperative Chemotherapy Followed by Surgery the Appropriate Treatment for Signet Ring Cell Containing Adenocarcinomas of the Esophagogastric Junction and Stomach?. Ann Surg Oncol 21, 1739–1748 (2014). https://doi.org/10.1245/s10434-013-3462-z

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-3462-z

Keywords

  • Gastric Cancer
  • Peritoneal Carcinomatosis
  • Signet Ring Cell
  • Circumferential Resection Margin
  • Signet Ring Cell Carcinoma