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Hindawi International Journal of Surgical Oncology Volume 2020, Article ID 8406045, 7 pages https://doi.org/10.1155/2020/8406045 Research Article The Effect of Lymph Nodes’ Histologic Response on Survival Outcomes in Moroccan Patients with Rectal Cancer 1,2,3 1,2 4 Ihsane El Otmani , Fatima El Agy , Mohammed El Abkari, 5 5 5 5 Karim Ibn Majdoub Hassani, Khalid Mazaz, El Bachir Benjelloun, Khalid Ait Taleb, 6 7 5 1,2 Touria Bouhafa, Zineb Benbrahim , Sidi Adil Ibrahimi, and Laila Chbani Laboratory of Biomedical and Translational Research. University of Medicine and Pharmacy of Fez, University Sidi Mohammed Ben Abdellah of Fez, 30070 Fez, Morocco Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, 30070 Fez, Morocco Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, 30070 Fez, Morocco Department of Gastroenterology, University Hospital Hassan II, 30070 Fez, Morocco Department of General Surgery, University Hospital Hassan II, 30070 Fez, Morocco Department of Radiotherapy, University Hospital Hassan II, 30070 Fez, Morocco Department of Oncology, University Hospital Hassan II, 30070 Fez, Morocco Correspondence should be addressed to Ihsane El Otmani; firstname.lastname@example.org Received 2 October 2019; Revised 15 November 2019; Accepted 10 December 2019; Published 6 January 2020 Academic Editor: Steven Curley Copyright © 2020 Ihsane El Otmani et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Prognosis for patients with locally advanced rectal cancer remains controversial. (e purpose of this study was to elucidate possible association between therapeutic eﬀect on lymph nodes (LNs) and patient prognosis. Overall, 149 patients with rectal cancer received preoperative radiotherapy in concomitance with chemotherapy or exclusive radiotherapy before rectal excision. Microscopic examination of formalin-ﬁxed lymph nodes was assessed for therapeutic eﬀect. (e establishment of groups combined reaction tissue types of ﬁbrosis, colloid, and necrosis after neoadjuvant treatment was assigned. (e average age was 56.38 years, ranged between 22 and 88 years, 53% were female, and 47% were men, with a sex ratio of 1 :12. In the present study, we noticed that after a median follow-up time of 40.67 months (0–83; SD: 21.1), overall survival was statistically signiﬁcant depending on age groups. Kaplan–Meier analysis showed signiﬁcant diﬀerences in the rate of patients with an age under 65 years (70.64%) versus those with an age over 85 years (36.5%) (p< 0.001). Also, the OS was statistically signiﬁcant depending on therapeutic eﬀect groups composed of 0TE (No (erapeutic eﬀect), C+ (presence of only colloidal eﬀect), F+ (presence of only ﬁbrosis tissue), and ME+ (mixture of 2 or 3 types of therapeutic eﬀect) group. Indeed, we observed a signiﬁcantly higher OS rate in the ME + group (86%) compared with the OS rate of LNs group with no therapeutic eﬀect (57%) (p � 0.028). Additionally, there was a signiﬁcant association between the presence of ﬁbrosis on LNs and an extended delay of more than 8 weeks to neoadjuvant treatment completion and surgery. Our study indicates that the best patient prognosis could be predicted based on tumor presenting a best pathologic eﬀect on lymph nodes, and that delaying surgery for more than 8 weeks to neoadjuvant treatment completion improves therapeutic response on LNs. cancers . (e standard treatment for patients with ad- 1. Introduction vanced rectal cancer is preoperative chemoradiotherapy or Rectal cancer (RC) is one of the most common cancers in radiotherapy followed by surgery. (is strategy allows to incidence and mortality in the world [1, 2]. RC presents 40% decrease the tumor size as well as to increase the degree of of colorectal cancer and approximately 20% of digestive tumor response to neoadjuvant treatment . Furthermore, 2 International Journal of Surgical Oncology Neoadjuvant therapy Surgical treatment Fibrosis Harvested Resected Dvorak Necrosis lymph specimens TRG (0, 1, 2, 3, 4) Colloid nodes (a) Category regression approach LNs regression 5 groups of Fibrosis Colloid Necrosis status regression + – –F+ F+ – + –C+ C+ – – + N+ None + + +3+ ME – + +2+ + + – 2+ + – +2+ – – – 0TE 0TE (b) Figure 1: Illustration of lymph nodes regression on categorical approach. (a) Chart illustration of patient strategy enrollment. (b) As- signment of categorical regression approach, deﬁning lymph nodes regression status. TE: therapeutic eﬀect; LNs: lymph nodes; 0TE: absence of therapeutic eﬀect; 2+: combination of two therapeutic eﬀect types; 3+: combination of three therapeutic eﬀect types; F+: ﬁbrosis eﬀect; C+: colloid eﬀect; N+: necrosis eﬀect; ME: mixed eﬀect. the prognosis of patients with RC can be estimated based on eﬀect on lymph nodes after neoadjuvant treatment followed various factors, such as tumor regression grading (TRG), by surgical procedure. vascular invasion, and perineural invasion [5, 6]. Lymph node (LN) status appears to occupy a more critical role in 2. Patients and Methods therapeutic strategy decisions after surgical procedure . (erefore, the presence of positive lymph nodes is consid- 2.1. Patients Enrollment. Consecutive 149 patients diag- ered to be a poor prognosis value of metastasis and re- nosed for rectal cancer were enrolled in this study, at currence . Semiquantitative evaluation of primary tumor HASSAN II University Hospital Center of Fez. Patients regression on surgical specimens, after neoadjuvant treat- underwent curative treatment based on proper surgery ment, was assessed by diﬀerent systems . (e therapeutic preceded by neoadjuvant exclusive radiotherapy (RT) or eﬀect on lymph nodes and primary tumor has been pro- neoadjuvant chemoradiotherapy (CRT). Fresh specimens posed as an indicator to select patients who may be at risk for were transported to the department of pathology for speciﬁc recurrence and metastasis for patients with rectal cancer procedures. Demographic and clinicopathological charac- . Unfortunately, none of these have been suﬃciently teristics were collected from the pathologic database of the informative for inclusion in clinical practice as recom- laboratory of anatomic pathology of HASSAN II University mended in breast cancer classiﬁcation by several authors [11, Hospital of Fez as well as the preoperative medical records as 12]. Additionally, interval between neoadjuvant therapy described in Figure 1(a). completion and surgery procedure has an eﬀect on tumor shrinkage as well as downstaging . Altogether, therapeutic eﬀect on LNs, in addition to the 2.2. Microscopic Lymph Nodes 1erapeutic Eﬀect Evaluation. duration between the end of neoadjuvant therapy and Gastrointestinal pathologists assessed lymph nodes evalu- surgery, could be proposed as a new challenge raised to ation procedure. (e LNs were identiﬁed by manual pal- become a part of the individualized therapy of rectal cancer pation and macroscopic examination through mesorectum indicated in clinical oncology. cut into tight sections and then retrieved entirely and placed Herein, we aim to describe the therapeutic eﬀect on LNs in separate cassettes. LNs evaluation was performed after after neoadjuvant treatment and to verify the hypothesis 10% formalin ﬁxation for a period of 48 hours, which could suggesting that prognostic value depends on therapeutic be extended to 72 hours if necessary. International Journal of Surgical Oncology 3 Table 1: Patient and therapeutic eﬀect on lymph nodes characteristics. Number of patients (%) Age 65 102 (68.45) 65–75 28 (18.8) 75–85 17 (11.4) 85 2 (1.35) Sex Men 70 (46.97) Women 79 (53.03) Histologic type Adenocarcinoma 145 (97.3) Mucinous/signet ring cell 4 (2.7) Figure 2: H&E staining showing a necrosis eﬀect on lymph node Degree of diﬀerentiation after neoadjuvant treatment (magniﬁcation: ×200). Well 72 (48.3) Moderate 69 (46.3) Poor 8 (5.4) 1.0 (erapeutic response on surgical specimen Complete response 25 (16.8) 0.8 Incomplete response 124 (83.2) (erapeutic eﬀect on surgical specimen according to the percentage of tumor regression 0.6 Presence 137 (92) Absence 12 (8) 0.4 Fibrosis TE on LNs Presence 133 (89.3) 0.2 Absence 16 (10.7) p < 0.001 Colloid TE on LNs Presence 99 (66.5) 0.0 Absence 50 (33.5) 0 20 40 60 80 100 Necrosis TE on LNs Time (months) Presence 91 (61.07) Age groups Absence 58 (38.93) <65 0-censure Regression types grouped on 5 65–75 1-censure 0TE 12 (8.1) 75–85 2-censure 2+ 8 (5.4) >85 3-censure 3+ 89 (59.8) F+ 36 (24) Figure 3: Kaplan–Meier curves for the duration in months of OS C+ 4 (2.7) according to patient’s age groups. Regression types grouped on 4 0TE 12 (8.1) F+ 36 (24.2) corresponds to the presence of only ﬁbrosis, C+ to the C+ 4 (2.7) presence of only colloidal tissue, N+ to the presence of only ME+ 97 (65) necrosis, and 2+ and 3+ correspond, respectively, to the TE: therapeutic eﬀect; LNs: lymph nodes; 0TE: absence of therapeutic eﬀect; presence of combined 2 and 3 therapeutic eﬀect types, as 2+: combination of two therapeutic eﬀect types; 3+: combination of three described in Figure 1(b). Association of tumor regression therapeutic types; F+: ﬁbrosis eﬀect; C+: colloid eﬀect. types with overall survival and relapse-free survival was analyzed. Standard hematoxylin-eosin staining was used to assess histologic examination on microscopic sections of tissue 2.3. Ethic Statement. (e local ethics committee at the samples and LNs. Pathologic grading was evaluated Faculty of Medicine and Pharmacy of Fez and Hassan II according to the TNM (tumor-node-metastasis) staging University Hospital reviewed and approved the research th system of the 7 version . protocol under the number 26/17. Ethical standards of the Presence of ﬁbrosis with mucous substance, colloid Helsinki Declaration were respected, and informed consent reaction, and necrosis tissue was considered as three types was obtained from all patients. of tumor response of LNs to neoadjuvant therapy. Eval- uation of tumor regression was assessed by qualitative estimation of presence or absence of one or mixed reaction 2.4. Follow-Up. (e starting point of the calculation of OS types (2 or 3 tumor type regression combined). F+ and RFS was on 01 January 2012, and the ﬁnal peak date was Overall survival 4 International Journal of Surgical Oncology Table 2: Univariate analysis for OS and RFS among patients with rectal cancer according to diﬀerent characteristics. Overall survival Relapse-free survival Characteristics OS (%) 95% CI p RFS (%) 95% CI p Age 65 70.64 65.74–75.55 <0.001 NA — 0.427 65–75 72.46 64.43–80.49 NA — 75–85 69.19 57.80–80.58 NA — 85 36.50 0.00–15.32 NA — Sex Men 69.75 63.49–76.01 0.600 59.46 50.99–67.92 0.684 Women 69.53 64.10–74.96 60.18 52.54–67.81 Histologic type Adenocarcinoma 70.71 66.50–74.91 0.607 NA — Mucinous/signet ring cell 57.00 24.74–89.25 NA — (erapeutic eﬀect Absence 47.31 33.53–61.09 0.041 36.21 18.53–53.89 0.098 Presence 71.69 67.52–75.85 61.74 55.82–67.88 Fibrosis TE on LNs Absence 58.84 42.45–75.23 0.038 49.57 27.70–71.44 0.300 Presence 70.27 66.23–74.31 60.06 54.25–65.87 Colloid TE on LNs Absence 61.69 53.27–70.10 0.001 54.66 44.23–65.10 0.279 Presence 74.15 69.79–78.51 62.74 55.98–69.50 Necrosis TE on LNs Absence 63.62 55.74–71.50 0.009 58.42 48.67–68.17 0.549 Presence 73.26 69.07–77.44 60.30 53.33–67.26 Regression types grouped on 5 0.427 0TE 47.31 33.53–61.09 0.051 2+ 71.80 64.43–79.16 NA — 3+ 73.11 68.84–77.38 NA — C+ 60.00 24.79–95.20 NA — F+ 62.81 53.19–72.43 NA — Regression types grouped on 4 0.331 0TE 47.31 33.53–61.09 0.028 NA — C+ 60.00 24.79–95.20 NA — F+ 62.81 53.19–72.43 NA — ME+ 72.98 68.86–77.09 NA — TE: therapeutic eﬀect; LNs: lymph nodes; 0TE: absence of therapeutic eﬀect; 2+: combination of two therapeutic eﬀect types; 3+: combination of three therapeutic types; F+: ﬁbrosis eﬀect; C+: colloid eﬀect; NA: not applicable. 30 October 2018. Overall survival (OS) was deﬁned as the young with a proportion of 68% (n � 102) under 65 years. time interval from the date of diagnosis until the date of Among all patients, 97.3% were classiﬁed as adenocarci- death from any cause and was censored at the last follow-up noma, and 2.7% were mucinous and signet ring cell if no death was recorded. Relapse-free survival (RFS) was carcinoma. deﬁned as the time between the diagnosis of the ﬁrst local recurrence and distant metastasis. 3.2. 1erapeutic Eﬀect Characteristics. (e therapeutic eﬀect was described as the presence of ﬁbrosis, necrosis, and 2.5. Statistical Analysis. Eﬀect of tumor regression on colloid changes after therapeutic eﬀect on LNs as shown in overall survival (OS) and relapse-free survival (RFS) were Figure 2. Among the diﬀerent grouped eﬀects, we found estimated using Kaplan–Meier curves. p≤ 0.05 was con- that ﬁbrosis reaction was assessed in 133 cases (91.3%) sidered statistically signiﬁcant. For statistical analysis, SPSS associated or not with other therapeutic eﬀect types. 21 (Statistical Package for Social Science) was used. Colloid changes were found in 66% of cases associated or not with ﬁbrosis and necrosis, while necrosis was asso- 3. Results ciated in all cases with ﬁbrosis and necrosis eﬀect at a rate of 60.7% (Table 1). 3.1. Patients’ Characteristics. Patients and tumor charac- teristics at baseline are described in Table 1. (is study consisted of 79 (52.7%) women and 70 (46.7%) men, with a 3.3. Prognostic Value of 1erapeutic Eﬀect. (e median fol- sex ratio of 1.12. (e majority of the population studied was low-up time was 40.67 months (0–83; SD: 21.1). (e OS was International Journal of Surgical Oncology 5 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 0 20 40 60 80 100 0 20 40 60 80 100 Time (months) Time (months) Colloid Fibrosis C– 0-censure F– 0-censure 1-censure C+ 1-censure F+ (a) (b) 1.0 0.8 0.6 0.4 0.2 0.0 0 20 40 60 80 100 Time (months) Necrosis N– 0-censure 1-censure N+ (c) Figure 4: Kaplan–Meier curves for the duration in months of OS according to the (a) presence of colloid (C+: presence of colloid and C−: absence of colloid), (b) presence of ﬁbrosis (F+: presence of ﬁbrosis and F−: absence of ﬁbrosis), and (c) necrosis eﬀect (N+: presence of necrosis and N−: absence of necrosis). found to be statistically signiﬁcant depending on age groups eﬀect (p � 0.028). RFS associated with diﬀerent character- as shown in Figure 3. (e OS rate of patients with an age istics did not show statistical signiﬁcance in all the analyses. under 65 years was 70.64% versus 36.5% of those with an age Data related to the interval between neoadjuvant therapy over 85 years (p< 0.001) (Table 2). (e presence of thera- and surgery were available for 123 cases. (e median interval peutic eﬀect of ﬁbrosis, colloid, and necrosis was statistically between the end of neoadjuvant therapy and surgery was 8 associated with prolonged OS, (p � 0.038, p � 0.001, and weeks (SD: 8.1, interval: 2 to 63 weeks). 40.7% (n � 50) of p � 0.009), respectively, as observed in Figure 4. When patients underwent surgery in less than 8 weeks versus 59.3% grouping therapeutic eﬀect on 4 groups of 0TE (no thera- (n � 73) after 8 weeks. (e analysis of the eﬀect of duration peutic eﬀect), C+ (presence of only colloidal eﬀect), F+ time between the end of neoadjuvant treatment and surgery (presence of only ﬁbrosis tissue) and ME+ (mixed of 2 or 3 on the presence of each type of responses in LNs showed a types of reaction) the OS was statistically signiﬁcant. Indeed, signiﬁcant association between an extended delay and the we observed a high OS rate (86%) in the ME + group com- presence of ﬁbrosis. 95.9% of patients who underwent pared with a low OS rate (57%) for LNs without therapeutic surgery after more than 8 weeks to the end of neoadjuvant Overall survival Overall survival Overall survival 6 International Journal of Surgical Oncology Table 3: (e eﬀect of neoadjuvant to surgery interval on the treatment express ﬁbrosis eﬀect on LNs (p � 0.014) as therapeutic eﬀect type. shown in Table 3. Delay between the end of 4. Discussion neoadjuvant treatment and (erapeutic eﬀect p value surgery Neoadjuvant treatment based on exclusive radiotherapy or <8 weeks >8 weeks chemoradiotherapy followed by surgical resection is the Fibrosis 0.014 current practice in locally advanced rectal cancer (T3 or T4 Absence 9 (18%) 3 (4.1) tumors, with or without lymph nodes metastasis) . Presence 41 (82%) 70 (95.9%) Lymph node status is recently the powerful indicator factor Necrosis 0.259 for prognosis in posttherapeutic rectal cancer [8, 16]. Absence 23 (46%) 25 (34.2%) General guidelines recommend the evaluation of a number Presence 27 (54%) 48 (65%) of 12 regional LNs to validate an accurate ypN0 status [4, 14, Colloid 0.703 15]. Unfortunately, until today, there are no particular Absence 16 (32%) 26 (35.6%) recommendations focusing on the histologic response on Presence 34 (68%) 47 (64.4%) retrieved LNs in rectal cancer after neoadjuvant treatment. In this purpose, we determined a therapeutic eﬀect in LNs, based on histological examination, likely to be a et al. demonstrated in their study that a delay greater than 8 prognostic factor. Furthermore, we suggest a consideration weeks was statistically correlated with the complete of nodal histologic response within the staging system for pathologic response . In our series, we proved that rectal cancer and in the ﬁnal report of pathologists. patients operated after a delay greater than 8 weeks to the Several grading systems have been proposed for TRG. neoadjuvant therapy express more ﬁbrosis therapeutic eﬀect on LNs. Ryan et al. , Mandard et al. , and Dworak et al.  TRG grading systems are systematically and frequently used Indeed, the most consistent predictive system of prog- nosis and pathologic response after neoadjuvant treatment is as recommended references, while these systems indicate low reproducibility and concordance in results among the pathologic staging system, when sided in complete re- gastrointestinal pathologists and did not include lymph node sponse and incomplete response. pathologic response . Our investigation has accurately predicted overall sur- In our study, we found that a better overall survival was vival in patients who have received primary neoadjuvant associated with the presence of combined histologic response treatment for rectal cancer. (is should be included in allowed by two or all ﬁbrosis, necrosis, and colloid compared pathologist reports and taken into consideration by clini- with the group without therapeutic eﬀects. (e more the cians in the therapeutic management after surgery. combination is large the better is the survival. Soo Hee Kim has established a modiﬁed Dworak TRG 5. Conclusion system for the estimation of histologic response in combi- (is study suggests that the best patient survival outcome is nation between the primary tumor and regional lymph related to tumors presenting the best pathologic eﬀect on nodes. He compared the predictive value of diﬀerent systems nodal tissue. Moreover, pathologic response on regional LNs of TRG, as Dvorak, Rayan, AJCC, and mDworak TRG may be an enhancer for the prognostic value of TRG systems systems. Kim et al. concluded that overall survival and re- evaluating the primary tumor separately. Delaying surgery lapse-free survival can be better predicted using combina- for more than 8 weeks to neoadjuvant treatment completion tion of ypStage and the modiﬁed Dworak TRG than using improves therapeutic response on lymph nodes. ypStage separately . 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International Journal of Surgical Oncology – Hindawi Publishing Corporation
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