Histopathological Parameters After Neoadjuvant Therapy in Rectal Tumors and Their Relationship With Treatment Response and Prognosis

Öz

Objective: This study aimed to evaluate histopathological parameters following neoadjuvant therapy in rectal adenocarcinoma and their associations with treatment response and survival outcomes. Materials and Methods: A total of 65 patients with rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy followed by surgical resection between 2007 and 2018 were retrospectively analyzed. Histopathological features, including tumor budding, poorly differentiated clusters (PDC), lymphovascular invasion (LVI), perineural invasion (PNI), circumferential resection margin (CRM) status, depth of invasion, and lymph node involvement, were re-evaluated. Tumor regression was graded using the Ryan tumor regression system and dichotomized into good (Grade 0–1) and poor (Grade 2–3) response groups. Survival analyses were performed using the Kaplan–Meier method. Results: Fourteen cases (21.5%) demonstrated a good response, whereas 51 (78.5%) showed a poor response. High tumor budding was significantly associated with reduced treatment response (p = 0.002). Perineural invasion and CRM positivity were significantly associated with worse overall survival (p = 0.001 and p = 0.014, respectively). Lymph node metastasis and greater depth of invasion showed trends toward poorer survival outcomes, although statistical significance was not reached. Patients older than 55 years had significantly longer disease-free survival (p = 0.021). Although favorable pathological response was associated with improved survival curves, this difference was not statistically significant. Conclusion: Tumor budding, perineural invasion, and CRM positivity are important prognostic indicators in rectal adenocarcinoma following neoadjuvant therapy. Comprehensive histopathological evaluation of post-treatment specimens plays a critical role in predicting treatment response and long-term outcomes.

Anahtar Kelimeler

• Rectal cancer
• neoadjuvant chemoradiotherapy
• tumor regression grading
• tumor budding
• perineural invasion
• circumferential resection margin

Kaynakça

1. 1. Siegel RL, Miller KD, Sauer AG, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–164. https://doi.org/10.3322/caac.21601
2. 2. Benson AB, Venook AP, Adam M, Chang G, Chen YJ, Ciombor KK, et al. NCCN Guidelines Insights: Rectal Cancer, Version 3. 2024. J Natl Compr Canc Netw. 2024;22(6):366–375. https://doi.org/10.6004/jnccn.2024.0041
3. 3. Delitto D, Loftus TJ, Iqbal A. Pathologic stage dictates survival after neoadjuvant radiation for rectal cancer. Oncotarget. 2018;9(84):35474–35475. https://doi.org/10.18632/oncotarget.26262
4. 4. Kuo LJ, Liu MC, Jian JJM, Horng CF, Cheng TI, Chen CM, et al. Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy? Ann Surg Oncol. 2007;14(10):2766–2772. https://doi.org/10.1245/s10434-007-9471-z
5. 5. Mahmoud NN. Colorectal cancer: preoperative evaluation and staging. Surg Oncol Clin N Am. 2022;31(2):127–141. https://doi.org/10.1016/j.soc.2021.12.001
6. 6. Chapman BC, Goodman K, Hosokawa P, Gleisner A, Cowan ML, Birnbaum E, et al. Improved survival in rectal cancer patients treated with long-course versus short-course neoadjuvant radiotherapy. J Surg Oncol. 2019;119(4):518–531. https://doi.org/10.1002/jso.25355
7. 7. Mahvi DA, Liu R, Grinstaff MW, Colson YL, Raut CP. Local cancer recurrence: realities, challenges, and opportunities for new therapies. CA Cancer J Clin. 2018;68:488–505. https://doi.org/10.3322/caac.21498
8. 8. Laohawiriyakamol S, Chaochankit W, Wanichsuwan W, Kanjanapradit K, Laohawiriyakamol T. Tumor regression grade and 5-year overall survival in locally advanced rectal cancer. Ann Coloproctol. 2023;39(1):59–70. https://doi.org/10.3393/ac.2021.01011.0144

9. 9. Rullier A, Laurent C, Capdepont M, Vendrely V, Belleannée G, Bioulac-Sage P, et al. Impact of tumor response on survival after radiochemotherapy in locally advanced rectal carcinoma. Am J Surg Pathol. 2010;34(4):562–568. https://doi.org/10.1097/PAS.0b013e3181d438b0
10. 10. Li JY, Huang XZ, Gao P, Song YX, Chen XW, Lv XE, et al. Survival landscape of tumor regression grades and pathological complete response after neoadjuvant therapy in rectal cancer. BMC Cancer. 2021;21:1214. https://doi.org/10.1186/s12885-021-08922-1
11. 11. Sugumar K, Lie JJ, Stucky CC, Chang YH, Brady J, Wasif N, et al. Pathologic complete response and survival in rectal cancer: a systematic review and meta-analysis. JAMA Netw Open. 2025;8(7):e2521197. https://doi.org/10.1001/jamanetworkopen.2025.21197
12. 12. Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ, et al. Long-term outcome in patients with pathological complete response after chemoradiation for rectal cancer. Lancet Oncol. 2010;11(9):835–844. https://doi.org/10.1016/S1470-2045(10)70172-8
13. 13. van Wyk HC, Roseweir A, Alexander P, Park JH, Horgan PG, McMillan DC, et al. Tumor budding, tumor microenvironment, and survival in colorectal cancer. Ann Surg Oncol. 2019;26(13):4397–4404. https://doi.org/10.1245/s10434-019-07931-6
14. 14. Cho MS, Bae HW, Kim NK. Essential knowledge and technical tips for total mesorectal excision in rectal cancer. Ann Coloproctol. 2024;40(4):384–411. https://doi.org/10.3393/ac.2024.00388.0055
15. 15. Detering R, Rutgers MLW, Bemelman WA, Hompes R, Tanis PJ. Prognostic importance of circumferential resection margin in rectal cancer: a systematic review and meta-analysis. Surgery. 2021;170(2):412–431. https://doi.org/10.1016/j.surg.2021.02.029
16. 16. Hugen N, Voorham QJM, Snaebjornsson P, Nagtegaal ID, Beets GL, Loughrey MB. Mode of circumferential margin involvement and its impact on outcomes in rectal cancer. Eur J Surg Oncol. 2024;50:108598. https://doi.org/10.1016/j.ejso.2024.108598
17. 17. Yu L, Yuan J, Lou S, Huang A, Cai X, Ji J, et al. Factors affecting survival in colorectal cancer: an umbrella review. J Transl Med. 2025;23:1185. https://doi.org/10.1186/s12967-025-06876-7
18. 18. Rafiee A, Nasri P, Moradi A, Karimian P. Tumor budding as a prognostic indicator after neoadjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Front Oncol. 2025;15:1429319. https://doi.org/10.3389/fonc.2025.1429319
19. 19. Ueno H, Murphy J, Jass JR, Mochizuki H, Talbot IC. Tumour budding as an index of aggressiveness in rectal cancer. Histopathology. 2002;40(2):127–132. https://doi.org/10.1046/j.1365-2559.2002.01324.x
20. 20. Vuik FE, Nieuwenburg SA, Bardou M, Lansdorp-Vogelaar I, Dinis-Ribeiro M, Bento MJ, et al. Increasing incidence of colorectal cancer in young adults in Europe. Gut. 2019;68(10):1820–1826. https://doi.org/10.1136/gutjnl-2018-317592
21. 21. Yeo SG, Kim DY, Kim TH, Chang HJ, Oh JH, Park W, et al. Prognostic significance of nodal status after chemoradiotherapy in rectal cancer. Ann Surg. 2010;252(6):998–1004. https://doi.org/10.1097/SLA.0b013e3181f3f1b1
22. 22. Abbaspour E, Karimzadhagh S, Monsef A, Joukar F, Mansour-Ghanaei F, Hassanipour S. Radiomics for prediction of lymph node metastasis in colorectal cancer: a systematic review and meta-analysis. Int J Surg. 2024;110:3795–3813. https://doi.org/10.1097/JS9.0000000000001239
23. 23. Dekker JWT, Peeters KC, Putter H, Vahrmeijer AL, van de Velde CJH. Metastatic lymph node ratio in stage III rectal cancer. Eur J Surg Oncol. 2010;36(12):1180–1186. https://doi.org/10.1016/j.ejso.2010.09.007
24. 24. Tan L, Liu ZL, Ma Z, He Z, Tang LH, Liu YL, et al. Prognostic impact of lymph node yield after neoadjuvant therapy in rectal cancer: a meta-analysis. World J Gastrointest Oncol. 2020;12(12):1443–1455. https://doi.org/10.4251/wjgo.v12.i12.1443
25. 25. Kim CH, Yeom S-S, Lee SY, Kim HR, Kim YJ, Lee KH, et al. Prognostic impact of lymphovascular invasion after neoadjuvant chemoradiotherapy. World J Surg 2019;43:260–272. https://doi.org/10.1007/s00268-018-4774-8
26. 26. Koukourakis IM, Kouloulias V, Tiniakos D, Georgakopoulos I, Zygogianni A. Current status of locally advanced rectal cancer therapy and future prospects. Crit Rev Oncol Hematol. 2023;186:103992. https://doi.org/10.1016/j.critrevonc.2023.103992
27. 27. Das P, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Hoff PM, et al. Clinical and pathologic predictors of recurrence and survival in rectal cancer after chemoradiotherapy. Am J Clin Oncol. 2006;29(3):219–224. https://doi.org/10.1097/01.coc.0000214930.78200.4a
28. 28. Weiser MR. AJCC 8th edition: colorectal cancer. Ann Surg Oncol. 2018;25(6):1454–1455. https://doi.org/10.1245/s10434-018-6462-1