Histopathology of residual rectal carcinoma following preoperative radiochemotherapy

Preoperative radiotherapy with (CRT) or without chemotherapy (RT) in the management of patients with locally advanced rectal carcinoma is increasingly accepted as therapeutic modality to reduce local recurrence and improve survival, decrease tumor size and/or stage, has less toxicity compared to postoperative therapy, improves sphincter preservation and the ability to perform a curative resection. In a brief review of literature we discussed the possible prognostic role of most important pathologic parameters and their clinical implications. At present, predictive value of tumor response to neoadjuvant therapy remains uncertain, whether evaluated as five-point histological tumor regression grade (TRG) or recently proposed three-point rectal cancer regression grade (RCRG). However, most reports emphasize reduced local reccurence rates and disease-free survival advantage in patients with complete tumour regression or tumour down-staging, occuring in up to 20% and 60% of cases, respectively. Patients with advanced post-treatment tumour stage (ypT3/4), positive lymph nodes (ypN1/2), vascular invasion, positive circumferential resection margin, clearance <2mm, or absence of tumor regression are shown to have poor clinical outcome. Among CRT-induced morphological features, only "fibrotic-type" stromal response with minimal inflammatory infiltrates and absence of surface ulceration are correlated to recurrence-free survival. Preliminary unpublished results of a pilot study from our multidisciplinary prospective trial relate to correlation of histopathologic parameters and morphologic changes to rectal cancer regression grade (RCRG). Therefore, we studied 22 consecutive patients, mean age 56 (range 23-69) years, with transmural cT3/4 stage and were subgrouped as follows: RCRG-1 (7 patients, 31,8%), RCRG-2 (9 patients, 40,9%) and RCRG-3 (6 patients, 27,2%). In addition, 14 patients (63%) showed tumour downstaging and only 1 patient (4,5%) nodal down-staging after ypTNM restaging. There was the predominance of fibrotic-type stroma (16 patients, 72,8%) versus fibro-inflammatory response (6 patients, 27,2%), frequent tumoral necrosis (13 patients, 59%) but infrequent surface ulceration (5 patients, 22,7%) and peritumoural eosinophylic infiltration as well as endocrine cell differentiation (4 patients, 18%). The second aim of our study was to investigate determinants of radiosensitivity, i.e. the relationship between proliferative activity indices (Ki- 67 and PCNA) as well as the induction of apoptosis (p53) and the tumour regression (RCRG) after neoadjuvant CRT. The interaction between Ki-67 and PCNA immunoexpression levels and the benefit of CRT was significant for Ki-67 (p = 0.03), but not for PCNA (p = 0.08) and p53 levels (p = 0.4). In a conclusion, high percentage of Ki-67-positive tumor cells in the preoperative biopsy predicts an decreased treatment response after preoperative CRT of rectal cancer. However, long-term follow-up and large studies are necessary to establish the value of regression grade and the need for its prediction by reliable biological markers.

Download Full-text

Histopathological evaluation of response to neoadjuvant chemoradiotherapy in locally advanced rectal carcinoma

Acta chirurgica iugoslavica ◽

10.2298/aci1601059m ◽

2016 ◽

Vol 63 (1) ◽

pp. 59-73

Author(s):

M. Micev ◽

M. Micev-Cosic ◽

Djikic Rom ◽

M. Andrejevic ◽

M. Dimic-Cumic ◽

...

Keyword(s):

Rectal Cancer ◽

Rectal Carcinoma ◽

Tumor Regression ◽

Histopathological Examination ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Tumour Regression ◽

Curative Therapy ◽

Complete Tumour ◽

Histologic Changes

Preoperative neoadjuvant chemoradiotherapy (nCRT) followed by radical surgical resection is the mainstay of curative therapy in the management of patients with locally advanced (stage II and III) rectal carcinoma in order to reduce local recurrence and improve survival following surgery for rectal cancer. A brief survey of histopathological tumor regression grading (TRG) systems, other histomorphological and immunohistochemical findings and their clinical implications were reported including authors? experience. Possible diagnostic pitfalls are discussed specially on complete tumour regression (pCR), differentiation downstaging and downsizing and other aspects of standard histopathological examination and RT-induced histologic changes, including morphological, immunohistochemical and molecular transdifferentiation of tumour cells. Some of these histopathological parameters have to be considered when auditing rectal cancer resections and identifying prognostic factors

Download Full-text

Over-Expression of CHD4 Is an Independent Biomarker of Poor Prognosis in Patients with Rectal Cancers Receiving Concurrent Chemoradiotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms20174087 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4087 ◽

Cited By ~ 5

Author(s):

Hui-Ching Wang ◽

Chia-Lin Chou ◽

Ching-Chieh Yang ◽

Wei-Lun Huang ◽

Yin-Chou Hsu ◽

...

Keyword(s):

Rectal Cancer ◽

Concurrent Chemoradiotherapy ◽

Tumor Regression ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumor Regression Grade ◽

Free Survival ◽

Node Metastasis ◽

Regression Grade

Neoadjuvant concurrent chemoradiotherapy (CCRT), followed by radical proctectomy, is the standard treatment for locally advanced rectal cancer. However, a poor response and therapeutic resistance continue to occur despite this treatment. In this study, we analyzed the microarray datasets (GSE68204) of rectal cancer from the Gene Expression Omnibus database, and identified CHD4 as one of the most significantly up-regulated genes among all subunits of the nucleosome remodeling and histone deacetylation (NuRD) complex, in non-responders to CCRT, among locally advanced rectal cancer (LARC) patients. We confirmed the predictive and prognostic significance of CHD4 expression in CCRT treatment, and its correlation with other clinicopathological features, such as tumor regression grade (TRG), therapeutic response, and patient survival. This was carried out by immunohistochemical studies on endoscopic biopsy tissues from 172 rectal cancer patients, receiving neoadjuvant concurrent chemoradiotherapy (CCRT). A high expression of CHD4 was significantly associated with pre-treatment tumor status (p < 0.001) and lymph node metastasis (p < 0.001), post-treatment tumor status (p < 0.001), and lymph node metastasis (p < 0.001), vascular invasion (p = 0.042), and tumor regression grade (p = 0.001). A high expression of CHD4 could also predict poor disease-specific survival and metastasis-free survival (log-rank test, p = 0.0373 and p < 0.0001, respectively). In multivariate Cox proportional-hazards regression analysis, CHD4 overexpression was an independent factor of poor prognosis for metastasis-free survival (HR, 4.575; 95% CI, 1.717–12.192; p = 0.002). By in vitro studies, based on cell line models, we also demonstrated that, the overexpression of CHD4 induced radio-resistance in microsatellite instability-high (MSI-H) colorectal cells (CRCs). On the contrary, the knockdown of CHD4 enhanced radiosensitivity in microsatellite stable (MSS) CRCs. Altogether, we have identified CHD4 as an important regulator of radio-resistance in both MSI-H and MSS CRC cell lines.

Download Full-text

Comparison of Tumor Regression Grade Systems for Locally Advanced Rectal Cancer After Multimodality Treatment

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/dju248 ◽

2014 ◽

Vol 106 (10) ◽

Cited By ~ 85

Author(s):

Atthaphorn Trakarnsanga ◽

Mithat Gönen ◽

Jinru Shia ◽

Garrett M. Nash ◽

Larissa K. Temple ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Locally Advanced ◽

Multimodality Treatment ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumor Regression Grade ◽

Regression Grade

Download Full-text

Prognostic Impact of the Neoadjuvant Rectal Score as Compared With the Tumor Regression Grade and Yield Pathologic TNM Stage in Patients With Locally Advanced Rectal Cancer After Neoadjuvant Chemoradiotherapy

In Vivo ◽

10.21873/invivo.11997 ◽

2020 ◽

Vol 34 (4) ◽

pp. 1993-1999

Author(s):

JIN HO BAEK ◽

DONG WON BAEK ◽

BYUNG WOOG KANG ◽

HYE JIN KIM ◽

SU YEON PARK ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tnm Stage ◽

Tumor Regression Grade ◽

Prognostic Impact ◽

Regression Grade

Download Full-text

Is there any significant difference between tumor regression grade systems of rectal cancer?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3583 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3583-3583

Author(s):

Atthaphorn Trakarnsanga ◽

Mithat Gonen ◽

Jinru Shia ◽

Garrett Michael Nash ◽

Larissa K. F. Temple ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Combined Modality Therapy ◽

Clinical Stage ◽

Locally Advanced ◽

Advanced Rectal Cancer ◽

Cancer Center ◽

Tumor Regression Grade ◽

Significant Difference ◽

Regression Grade

3583 Background: Tumor regression grade (TRG) is a measure of histopathologic response of rectal cancer to preoperative chemoradiation (CRT) and correlates with outcomes. Several TRG systems have been reported including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan Kettering Cancer Center (MSKCC), and American Joint Committee of Cancer (AJCC). The purpose of this study is to compare the different TRG systems and determine which one(s) best predict recurrence and survival. Methods: Review of prospective maintained database from 1998 to 2007 identified 563 patients with locally advanced rectal cancer (T3/4 and/or N1) and treated with long-course CRT followed by total mesorectal excision. TRG was determined by measuring proportion of tumor mass replaced by fibrosis. Patients were then classified into the various TRG schemes which were compared by analyzing association with recurrence and survival using concordance index (CI) and reclassification index. CI is a measure that summarizes the predictive strength of a marker. Computing and contrasting CI across several markers is a way of selecting the best prognostic marker. Results: 75% of patients were noted to have clinical stage III disease by endorectal ultrasound or rectal MRI. Following resection with median follow-up of 39.3 months, 2% developed local recurrence and 17% developed distant metastasis. The median interval time between completion of CRT and surgery is 48 days. 20% demonstarted complete pathological response. CI of the 3 tier Mandard, 3 tier Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694, respectively (higher number indicates better prediction). The AJCC was significantly more accurate in predicting recurrence than the 3- tier Mandard (p=0.002), and Dowrak/Rodel (p=0.006). AJCC had a higher CI than MSKCC although it did not reach significance (p=0.068). Comparing the 3 tier systems, MSKCC was most accurate and correctly reclassified 17 % and 23 % of the patients Mandard and Dowrak/Rodel systems, respectively. Conclusions: TRG predicts recurrence and survival following combined modality therapy for rectal cancer. The TRG system that recently was proposed in the 7thAJCC staging is currently the most accurate predictor.

Download Full-text

The prognosis valve of tumor regression grade in the same ypStage patients after neoadjuvant treatment in locally advanced rectal cancer: Post-hoc analysis of a prospective trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16129 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16129-e16129

Author(s):

Jianwei Zhang ◽

Yue Cai ◽

Huabin Hu ◽

Zehua Wu ◽

Xiaoyu Xie ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Locally Advanced ◽

Prospective Trial ◽

Neoadjuvant Treatment ◽

Disease Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumor Regression Grade ◽

Prognosis Factor

e16129 Background: The ypStage after neoadjuvant treatment was an important prognosis factor in locally advanced rectal cancer (LARC). pCR or ypStage 0 showed best prognosis, while ypStage II-III showed poor prognosis and further adjuvant chemotherapy with FOLFOX was recommended. Tumor regression grade (TRG) was another factor to evaluate the response to neoadjuvant treatment. Even in the same ypStage, the TRG could be different. Here, we tried to analyze the prognosis valve of TRG in the same ypStage after neoadjuvant treatment in LARC from a prospective trial (FOWARC study). Methods: Patients with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil plus radiotherapy followed by surgery and seven cycles of infusional fluorouracil as adjuvant treatment, the same treatment plus intravenous oxaliplatin 85 mg/m2 on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS). Survival analysis was performed on different ypStage and TRG (WHO classification) group. Results: In total, 495 patients were randomly assigned to different neoadjuvant treatment. 444 patients received surgery with a median follow-up of 45.2 months. The 3-year disease free survival (DFS) in ypStage 0, ypStage I, ypStage II and ypStage III was 95.8%, 89.2%, 71.7% and 55.1%, respectively (P < 0.0001). In TRG 0, 1, 2 and 3, the 3-year DFS was 93.3%, 83.2%, 68.4% and 63.6%, respectively (P < 0.0001). In ypStage I subgroup, TRG was not an independent prognosis factor, the 3-year DFS for TRG 1, 2 and 3 was 90.0%, 90.7% and 76.2%, respectively (P = 0.277). In ypStage II population, the 3-year DFS for TRG 1, 2 and 3 was 78.6%, 70.3% and 64.7%, respectively (P = 0.184). The ypStage III group showed great heterogeneity, the 3-year DFS for TRG 0-3 was 60.0%, 70.0%, 41.8% and 59.5%, respectively (P = 0.067). Conclusions: Both ypStage and TRG was strong prognosis factor for rectal cancer after neoadjuvant treatment. However, TRG was not an independent prognosis factor in the same ypStage after neoadjuvant treatment. Clinical trial information: NCT01211210 .

Download Full-text