Annals of Surgical Oncology

, Volume 24, Issue 4, pp 966–973 | Cite as

Prognostic Factors for Locoregional Recurrence in Patients with Thoracic Esophageal Squamous Cell Carcinoma Treated with Radical Two-Field Lymph Node Dissection: Results from Long-Term Follow-Up

  • ShiLiang Liu
  • Simone Anfossi
  • Bo Qiu
  • YuZhen Zheng
  • MuYan Cai
  • Jia Fu
  • Hong Yang
  • Qing Liu
  • ZhaoLin Chen
  • JianHua Fu
  • MengZhong Liu
  • Jared K. Burks
  • Steven H. Lin
  • James Reuben
  • Hui Liu
Gastrointestinal Oncology

Abstract

Objective

To aim of this study was to determine the clinical and biological prognostic factors for locoregional recurrence (LRR) in patients with thoracic esophageal squamous cell carcinoma (ESCC) undergoing radical two-field lymph node dissection (2FLD).

Methods

A total of 462 patients diagnosed with thoracic ESCC underwent radical esophagectomy between March 2001 and May 2010 at Sun Yat-Sen University Cancer Center. Clinical characteristics, CD44 expression, and tumor-infiltrating lymphocyte (TIL) levels were evaluated in 198 patients who underwent R0 dissection with long-term follow-up. Partial Cox regression analysis with leave-one-out cross-validation was performed to validate the selected risk factors.

Results

With a median follow-up of 54 months, the 5-year local failure-free survival (LFFS) rate of 198 patients was 62.5%. Multivariate analysis revealed that T stage (p = 0.043), pathological positive tumor above the carina (p = 0.000), CD44 expression level (p = 0.045) and TIL level (p = 0.007) were prognostic factors for LFFS, while the Cox model with risk scores had an area under the curve value of 83.6% for the prediction of 5-year LFFS. The best cut-off value (sum score = 11.19) was used to determine the high- and low-risk groups, with patients at high risk having a significantly shorter 5-year LFFS than patients at low risk (p = 0.000). The LRR pattern revealed significantly high incidences of recurrent disease at the supraclavicular and cervical sites, mediastinum (above the carina), and anastomosis.

Conclusions

Our predictive model was able to distinguish between patients at high risk for LRR and patients at low risk for LRR. LRR primarily involved the upper thorax and this area must be considered in future study designs for radical trimodality treatment.

References

  1. 1.
    Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  3. 3.
    Nakagawa S, Kanda T, Kosugi S, Ohashi M, Suzuki T, Hatakeyama K. Recurrence pattern of squamous cell carcinoma of the thoracic esophagus after extended radical esophagectomy with three-field lymphadenectomy. J Am Coll Surg. 2004;198:205–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Li H, Zhang Y, Cai H, Xiang J. Pattern of lymph node metastases in patients with squamous cell carcinoma of the thoracic esophagus who underwent three-field lymphadenectomy. Eur Surg Res. 2007;39:1–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Huang W, Li B, Gong H, Yu J, Sun H, Zhou T, et al. Pattern of lymph node metastases and its implication in radiotherapeutic clinical target volume in patients with thoracic esophageal squamous cell carcinoma: a report of 1077 cases. Radiother Oncol. 2010;95:229–33.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen J, Liu S, Pan J, Zheng X, Zhu K, Zhu J, et al. The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma. Eur J Cardiothorac Surg. 2009;36:480–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Ding X, Zhang J, Li B, Wang Z, Huang W, Zhou T, et al. A meta-analysis of lymph node metastasis rate for patients with thoracic oesophageal cancer and its implication in delineation of clinical target volume for radiation therapy. Br J Radiol. 2012;85:e1110–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Kieser M, Slanger TE, et al. Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data. Eur J Cancer 2013;49:3149–58.CrossRefPubMedGoogle Scholar
  9. 9.
    Lerut T, Nafteux P, Moons J, Coosemans W, Decker G, De Leyn P, et al. Three-field lymphadenectomy for carcinoma of the esophagus and gastroesophageal junction in 174 R0 resections: impact on staging, disease-free survival, and outcome: a plea for adaptation of TNM classification in upper-half esophageal carcinoma. Ann Surg. 2004;240:962–72.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, et al. Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. J Am Coll Surg. 2000;190:562–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Zoller M. CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 2011;11:254–67.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhao JS, Li WJ, Ge D, Zhang PJ, Li JJ, Lu CL, et al. Tumor initiating cells in esophageal squamous cell carcinomas express high levels of CD44. PLoS ONE 2011;6:e21419.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Biddle A, Gammon L, Fazil B, Mackenzie IC. CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition. PLoS ONE 2013;8:e57314.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Minato T, Yamamoto Y, Seike J, Yoshida T, Yamai H, Takechi H, et al. Aldehyde dehydrogenase 1 expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2013;20:209–17.CrossRefPubMedGoogle Scholar
  15. 15.
    Le Bras GF, Allison GL, Richards NF, Ansari SS, Washington MK, Andl CD. CD44 upregulation in E-cadherin-negative esophageal cancers results in cell invasion. PLoS ONE 2011;6:e27063.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Näsman A, Nordfors C, Grün N, Munck-Wikland E, Ramqvist T, Marklund L, et al. Absent/weak CD44 intensity and positive human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma indicates a very high survival. Cancer Med. 2013;2:507–18.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ko YH, Won HS, Jeon EK, Hong SH, Roh SY, Hong YS, et al. Prognostic significance of CD44s expression in resected non-small cell lung cancer. BMC Cancer 2011;11:340.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Ohtani H. Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun. 2007;7:4.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32:2959–66.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Dieci MV, Mathieu MC, Guarneri V, Conte P, Delaloge S, Andre F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015;26:1698–1704.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol. 2013;31:4252–9.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zingg U, Montani M, Frey DM, Dirnhofer S, Esterman AJ, Went P, et al. Tumour-infiltrating lymphocytes and survival in patients with adenocarcinoma of the oesophagus. Eur J Surg Oncol. 2010;36:670–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res. 2003;63:1555–9.PubMedGoogle Scholar
  25. 25.
    Schumacher K, Haensch W, Roefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001;61:3932–6.PubMedGoogle Scholar
  26. 26.
    Ikeguchi M, Saito H, Katano K, Tsujitani S, Maeta M, Kaibara N. Correlation between the lymphocytic infiltration of tumors and the proliferative activity of cancer cells from surgically treated esophageal carcinoma. Oncology 1997;54:311–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Japanese Society for Esophageal Diseases. Clinicopathological aspects. In: Guidelines for clinical and pathologic studies on carcinoma of the esophagus. 9. Tokyo: Kanehara & Co., Ltd; 1999. pp. 1–34.Google Scholar
  28. 28.
    Tachimori Y, Nagai Y, Kanamori N, Hokamura N, Igaki H. Pattern of lymph node metastases of esophageal squamous cell carcinoma based on the anatomical lymphatic drainage system. Dis Esophagus 2011;24:33–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Nishihira T, Hirayama K, Mori S. A prospective randomized trial of extended cervical and superior mediastinal lymphadenectomy for carcinoma of the thoracic esophagus. Am J Surg. 1998;175:47–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Tachibana M, Kinugasa S, Yoshimura H, Dhar DK, Nagasue N. Extended esophagectomy with 3-field lymph node dissection for esophageal cancer. Arch Surg. 2003;138:1383–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Rizk N, Venkatraman E, Park B, Flores R, Bains MS, Rusch V, American Joint Committee on Cancer Staging System. The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg. 2006;132:1374–81.CrossRefPubMedGoogle Scholar
  32. 32.
    Urba SG, Orringer MB, Strawderman M, Turrisi A, Iannettoni M, Forastiere A. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19(2):305–13.CrossRefPubMedGoogle Scholar
  33. 33.
    Burmeister BH, Smithers BM, Denham JW, Gebski V, Fitzgerald L, Simes RJ, et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: A randomized controlled phase III trial. Lancet Oncol. 2005;6(9):659–68.CrossRefPubMedGoogle Scholar
  34. 34.
    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.Google Scholar
  35. 35.
    Oppedijk V, Van der Gaast A, Van Lanschot JJ, Van Hagen P, Van Os R, Van Rij CM, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol. 2014;32(5):385–91.CrossRefPubMedGoogle Scholar
  36. 36.
    Bourguignon LY. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol. 2008;18:251–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xu H, Tian Y, Yuan X, Liu Y, Wu H, Liu Q, et al. Enrichment of CD44 in basal-type breast cancer correlates with EMT, cancer stem cell gene profile, and prognosis. Oncotargets Ther. 2016;9:431–44.Google Scholar
  38. 38.
    Li X, Ma X, Chen L, Gu L, Zhang Y, Zhang F, et al. Prognostic value of CD44 expression in renal cell carcinoma: a systematic review and meta-analysis. Sci Rep. 2015;5:13157.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011;105:93–103.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Ténière P, Hay JM, Fingerhut A, et al. Postoperative radiation therapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicentered controlled trial. French University Association for Surgical Research. Surg Gynecol Obstet. 1991;173:123–30.PubMedGoogle Scholar
  41. 41.
    Fok M, Sham JS, Choy D, et al. Postoperative radiotherapy for carcinoma of the esophagus: a prospective, randomized controlled study. Surgery 1993;113:138–47.PubMedGoogle Scholar
  42. 42.
    Zieren HU, Muller JM, Jacobi CA, et al. Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus: a prospective randomized study. World J Surg. 1995;19:444–9.CrossRefPubMedGoogle Scholar
  43. 43.
    Schreiber D, Rineer J, Vongtama D, et al. Impact of postoperative radiation after esophagectomy for esophageal cancer. J Thorac Oncol. 2010;5(2):244–50.CrossRefPubMedGoogle Scholar
  44. 44.
    Chen J, Zhu J, Pan J, et al. Postoperative radiotherapy improved survival of poor prognostic squamous cell carcinoma esophagus. Ann Thorac Surg. 2010;90(2):435–42.CrossRefPubMedGoogle Scholar

Copyright information

© Society of Surgical Oncology 2016

Authors and Affiliations

  • ShiLiang Liu
    • 1
    • 5
    • 6
    • 7
  • Simone Anfossi
    • 8
  • Bo Qiu
    • 1
    • 5
    • 6
    • 7
  • YuZhen Zheng
    • 11
  • MuYan Cai
    • 3
    • 5
    • 6
    • 7
  • Jia Fu
    • 3
    • 5
    • 6
    • 7
  • Hong Yang
    • 2
    • 5
    • 6
    • 7
  • Qing Liu
    • 4
    • 5
    • 6
    • 7
  • ZhaoLin Chen
    • 1
    • 5
    • 6
    • 7
  • JianHua Fu
    • 2
    • 5
    • 6
    • 7
  • MengZhong Liu
    • 1
    • 5
    • 6
    • 7
  • Jared K. Burks
    • 9
  • Steven H. Lin
    • 10
  • James Reuben
    • 8
  • Hui Liu
    • 1
    • 5
    • 6
    • 7
  1. 1.Department of Radiation OncologySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  2. 2.Department of Thoracic SurgerySun Yat-Sen University Cancer CenterGuangzhouPeople’s Republic of China
  3. 3.Department of PathologySun Yat-Sen University Cancer CenterGuangzhouPeople’s Republic of China
  4. 4.Department of Clinical StatisticsSun Yat-Sen University Cancer CenterGuangzhouPeople’s Republic of China
  5. 5.State Key Laboratory of Oncology in South ChinaGuangzhouPeople’s Republic of China
  6. 6.Collaborative Innovation Center for Cancer MedicineGuangzhouPeople’s Republic of China
  7. 7.Guangdong Esophageal Cancer Research InstituteGuangzhouPeople’s Republic of China
  8. 8.Department of HematopathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  9. 9.Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonUSA
  10. 10.Department of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  11. 11.Department of Thoracic SurgeryFujian Provincial Tumor HospitalFuzhouPeople’s Republic of China

Personalised recommendations