Early Invasive Colorectal Cancer Research Articles

Low PD-L1 expression in immune cells predicts the presence of nodal metastasis in early invasive (pT1) colorectal cancer: a novel tool to tailor surgical treatment.

The current criteria for surgical treatment after endoscopic resection of a pT1 colorectal carcinoma (CRC) are unsatisfactory because nodal involvement is rarely present. This study investigates the correlation between PD-L1 expression and nodal metastasis in pT1 CRCs to enable its use for tailoring surgical treatment after endoscopic removal. Histopathological features of 81 surgically resected pT1 CRC, 19 metastatic and 62 non-metastatic cases were assessed. PD-L1 expression was evaluated by immunohistochemistry (clone 22C3) and independently assessed by two pathologists using tumour proportion score (TPS), combined positive score (CPS) and immune cell score (ICS). The correlation between PD-L1 expression and nodal metastasis, the optimal cut-off values, interobserver agreement and impact upon patients' surgical management were determined. PD-L1 expression in termsof CPS and ICS independently correlated with lymph node metastasis (PD-L1CPS : OR = -2.5, 95% CI = -4.11 to -0.97, P = 0.008 and PD-L1ICS : OR = -1.85, 95% CI = -2.90 to -0.79, P = 0.004) and < 1.2 CPS and <1.3% ICS were identified as the optimal cut-off values to discriminate between metastatic and non-metastatic patients. In our cohort, the implementation of these cut-off values would have avoided a significant rate of unnecessary surgeries in pN0 patients (PD-L1CPS = 43.2; PD-L1ICS = 51.9%). Ultimately, PD-L1 evaluation showed good interpathologist concordance in absolute terms [PD-L1CPS interclass correlation coefficient (ICC) = 0.91; PD-L1ICS ICC = 0.793] and using the identified cut-off values (PD-L1CPS ICC = 0.848; PD-L1ICS ICC = 0.756). Our study shows that PD-L1 expression is an effective predictor of nodal status and could improve patient selection for surgery after endoscopic removal of pT1 CRCs.

Tumour-stroma ratio has poor prognostic value in non-pedunculated T1 colorectal cancer: A multi-centre case-cohort study.

BackgroundCurrent risk stratification models for early invasive (T1) colorectal cancer are not able to discriminate accurately between prognostic favourable and unfavourable tumours, resulting in over‐treatment of a large (>80%) proportion of T1 colorectal cancer patients. The tumour‐stroma ratio (TSR), which is a measure for the relative amount of desmoplastic tumour stroma, is reported to be a strong independent prognostic factor in advanced‐stage colorectal cancer, with a high stromal content being associated with worse prognosis and survival. We aimed to investigate whether the TSR predicts clinical outcome in patients with non‐pedunculated T1 colorectal cancer.MethodsHaematoxylin and eosin (H&E)‐stained tumour tissue slides from a retrospective multicentre case cohort of patients with nonpedunculated surgically treated T1 colorectal cancer were assessed for TSR by two independent observers who were blinded for clinical outcomes. The primary end point was adverse outcome, which was defined as the presence of lymph node metastasis in the resection specimen or colorectal cancer recurrence during follow‐up.ResultsAll 261 patients in the case cohort had H&E slides available for TSR scoring. Of these, 183 were scored as stroma‐low, and 78 were scored as stroma‐high. There was moderate inter‐observer agreement κ = 0.42). In total, 41 patients had lymph node metastasis, 17 patients had recurrent cancer and five had both. Stroma‐high tumours were not associated with an increased risk for an adverse outcome (adjusted hazard ratio = 0.66, 95% confidence interval 0.37–1.18; p = 0.163).ConclusionsOur study emphasises that existing prognosticators may not be simply extrapolated to T1 colorectal cancers, even though their prognostic value has been widely validated in more advanced‐stage tumours.

Clinical management of endoscopically resected pT1 colorectal cancer.

Background Implementation of colorectal cancer (CRC) screening programs increases endoscopic resection of polyps with early invasive CRC (pT1). Risk of lymph node metastasis often leads to additional surgery, but despite guidelines, correct management remains unclear. Our aim was to assess the factors affecting the decision-making process in endoscopically resected pT1-CRCs in an academic center. Methods We retrospectively reviewed patients undergoing endoscopic resection of pT1 CRC from 2006 to 2016. Clinical, endoscopic, surgical treatment, and follow-up data were collected and analyzed. Lesions were categorized according to endoscopic/histological risk-factors into low and high risk groups. Comorbidities were classified according to the Charlson comorbidity index (CCI). Surgical referral for each group was computed, and dissociation from current European CRC screening guidelines recorded. Multivariate analysis for factors affecting the post-endoscopic surgery referral was performed. Results Seventy-two patients with endoscopically resected pT1-CRC were included. Overall, 20 (27.7 %) and 52 (72.3 %) were classified as low and high risk, respectively. In the low risk group, 11 (55 %) were referred to surgery, representing over-treatment compared with current guidelines. In the high risk group, nonsurgical endoscopic surveillance was performed in 20 (38.5 %) cases, representing potential under-treatment. After a median follow-up of 30 (6 – 130) months, no patients developed tumor recurrence. At multivariate analysis, age (OR 1.21, 95 %CI 1.02 – 1.42; P = 0.02) and CCI (OR 1.67, 95 %CI 1.12 – 3.14; P = 0.04) were independent predictors for subsequent surgery. Conclusions A substantial rate of inappropriate post-endoscopic treatment of pT1-CRC was observed when compared with current guidelines. This was apparently related to an overestimation of patient-related factors rather than endoscopically or histologically related factors.

Quality of life and fear of cancer recurrence in T1 colorectal cancer patients treated with endoscopic or surgical tumor resection

To optimize therapeutic decision-making in early invasive colorectal cancer (T1 CRC) patients, it is important to elicit the patient's perspective next to considering medical outcome. Because empirical data on patient-reported impact of different treatment options are lacking, we evaluated patients' quality of life, perceived time to recovery, and fear of cancer recurrence after endoscopic or surgical treatment for T1 CRC. In this cross-sectional study, we selected patients with histologically confirmed T1 CRC who participated in the Dutch Bowel Cancer Screening Programme and received endoscopic or surgical treatment between January 2014 and July 2017. Quality of life was measured using the European Organization for Research and Treatment 30-item Core Quality of Life Questionnaire and the 5-level EuroQoL 5-dimension questionnaire. We used the Cancer Worry Scale (CWS) to evaluate patients' fear of cancer recurrence. A question on perceived time to recovery after treatment was also included in the set of questionnaires sent to patients. Of all 119 eligible patients, 92.4% responded to the questionnaire (endoscopy group, 55/62; surgery group, 55/57). Compared with the surgery group, perceived time to recovery was on average 3 monthsshorter in endoscopically treated patients after adjustment for confounders (19.9 days vs 111.3 days; P= .001). The 2 treatment groups were comparable with regard to global quality of life, functioning domains, and symptom severity scores. Moreover, patients in the endoscopy group did not report more fearof cancer recurrence than those in the surgery group (CWS score, 0-40; endoscopy 7.6 vs surgery 9.7; P= .140). From the patient's perspective, endoscopic treatment provides a quicker recovery than surgery, without provoking more fear of cancer recurrence or any deterioration in quality of life. These results contribute to the shared therapeutic decision-making process of clinicians and T1 CRC patients.

Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers.

It is unclear whether somatic copy number alterations (SCNAs) contribute to the development of colorectal cancer (CRC). Here, we aimed to identify the molecular profiles of early colorectal carcinogenesis based on SCNAs and determine the associations of other molecular abnormalities for the detection of neoplasia in both intramucosal neoplasia (IMN) and invasive CRC with invasion into the muscular layer without metastasis (early invasive CRC). A single nucleotide polymorphism array was used to examine 100 colorectal IMNs (low-grade adenoma [LGA], 40; high-grade adenoma [HGA], 25; intramucosal adenocarcinoma [IMA], 35) and early invasive CRC (20 tumors). In addition, genetic mutations (KRAS, BRAF), TP53 overexpression, microsatellite instability (MSI), and DNA methylation (low, intermediate, high) were examined. Hierarchical clustering analysis based on the SCNA pattern was carried out to identify molecular profiles in IMNs and early invasive CRC. Colorectal tumors were classified into three subgroups based on SCNA patterns. Subgroup 1 was characterized by multiple SCNAs, subgroup 3 was closely associated with infrequent SCNAs, and subgroup 2 was an intermediate subgroup in SCNA pattern between subgroups 1 and 3. Although mutations in KRAS were commonly found in all three subgroups, overexpression of TP53 was observed primarily in subgroup 1 and 2. DNA methylation showed a low/intermediate type. Finally, no MSI was detected. Each subgroup was correlated with histology (subgroup 1, early invasive CRC; subgroup 2, LGA; subgroups 2 and 3, HGA and IMA). Considerable SCNAs may be required for acquisition of invasive ability in CRC. Our results provide novel insights into early CRC.

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Novel risk factors for lymph node metastasis in early invasive colorectal cancer: a multi-institution pathology review

Novel risk factors for lymph node metastasis (LNM) in T1 colorectal cancer (CRC) have been recently proposed, but most have not been implemented because of the lack of validation. Here we determined the value of poorly differentiated clusters (PDCs) in a multi-institutional cohort of T1 CRC cases. A pathology review involving 30 institutions was conducted for 3556 T1 CRCs. PDC was defined as malignant clusters comprising ≥5 cells and lacking a glandular formation. The ability to identify LNM risk was compared using Akaike's information criterion (AIC). PDC was observed in 1401 tumors (39.4 %), including 94 (17.8 %) with <1000 µm submucosal invasion and 1307 (43.2 %) with ≥1000 µm submucosal invasion (P < 0.0001). The incidence of LNM was higher in PDC-positive tumors (17.4 %) than in PDC-negative tumors (6.9 %; P < 0.0001), and PDCs had an adverse impact on LNM irrespective of the degree of submucosal invasion. Grade 3, vascular invasion, budding, and submucosal invasion depth were also significant factors (all, P < 0.0001). AIC of risk factor to identify LNM risk was most favorable for vascular invasion (2273.4), followed by PDC (2357.4); submucosal invasion depth (2429.1) was the most unfavorable. Interinstitutional judgment disparities were smaller in PDC (kappa, 0.51) than vascular invasion (0.33) or tumor grade (0.48). PDC is a promising new parameter with good ability to identify LNM risk. Use of its appropriate judgment criteria will enable us determine whether an observational policy can be safely applied following local tumor excision in T1 CRC cases.

Identification of Differentially-Expressed Proteins between Early Submucosal Non-Invasive and Invasive Colorectal Cancer Using 2D-DIGE and Mass Spectrometry

Early detection and diagnosis of colorectal cancer (CRC) are closely related to a better therapeutic outcome, and the five-year survival rate of early CRC is over 90 percent. Though endoscopic minimally invasive treatment has become a quick and effective therapy for early CRC, endoscopic biopsies are usually not deep enough to obtain tissues from the submucosal layer and it is difficult to determine whether early CRC has infiltrated into the submucosa. Therefore, in the present study, we constructed tumor models of early submucosal non-invasive CRC (SNICRC) and submucosal invasive CRC (SICRC) in Fischer-344 rats induced by N-methyl-N-nitrosourea (MNU). The differentially-expressed proteins were analyzed and identified in SNICRC, SICRC and normal control (NC) tissues using highly sensitive two dimensional differential gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS). Proteomic data revealed 132 protein spots between SNICRC and SICRC, 162 protein spots between SICRC and NC and 154 protein spots between SNICRC and NC which were found differentially expressed. These differential spots were picked, in-gel digested and peptide mass fingerprints were obtained by MALDITOF-MS/MS. Finally, five differentially-expressed proteins in SNICRC, SICRC and NC were identified, and increases in Transgelin, peptidylprolyl isomerase A (PPIA) and tropomyosin alpha isoform d were observed, while decreases in carbonic anhydrase 2 (CAII) and an unnamed protein were detected in SICRC compared with SNICRC and NC. Furthermore, Fluorescence-based quantitative polymerase chain reaction (FQ-PCR), Western blotting and immunohistochemistry assays also revealed significant upregulation of Transgelin expression and down-regulation of CAII expression in SICRC tissues. In conclusion, 2D-DIGE is confirmed to be an efficient strategy that enables us to identify differentially expressed proteins between early SNICRC and SICRC. The potential biomarkers such as Transgelin and CAII may be used for the detection of early SICRC.

Risk of lymph node metastasis in patients with pedunculated type early invasive colorectal cancer: A retrospective multicenter study

Depth of invasion in early invasive colorectal cancer is considered an important predictive factor for lymph node metastasis. However, no large-scale reports have established the relationship between invasion depth of pedunculated type early invasive colorectal cancers and risk of lymph node metastasis. The aim of this retrospective cohort study was to clarify the risk of lymph node metastasis in pedunculated type early invasive colorectal cancers in a large series. Patients with pedunculated type early invasive colorectal cancer who underwent endoscopic or surgical resection at seven referral hospitals in Japan were enrolled. Haggitt's line was used as baseline and the invasion depth was classified into two groups, head invasion and stalk invasion. The incidence of lymph node metastasis was investigated between patients with head and stalk invasion. We analyzed 384 pedunculated type early invasive colorectal cancers in 384 patients. There were 154, 156, and 74 endoscopic resection cases, endoscopic resection followed by surgical operation, and surgical resection cases, respectively. There were 240 head invasion and 144 stalk invasion lesions. Among the lesions treated surgically, the overall incidence of lymph node metastasis was 3.5% (8/230). The incidence of lymph node metastasis was 0.0% (0/101) in patients with head invasion, as compared with 6.2% (8/129) in patients with stalk invasion. Pedunculated type early invasive colorectal cancers pathologically diagnosed as head invasion can be managed by endoscopic treatment alone.

Proposed Objective Criteria for “Grade 3” in Early Invasive Colorectal Cancer

To establish objective criteria for "grade 3" (G3) in T1 (TNM staging) colorectal cancer (CRC), a total of 296 T1 CRC cases were reviewed. The incidence of nodal involvement differed most greatly between G3 and non-G3 (21/27 [27%] and 6/162 [3.7%], respectively; P < .0001), when G3 was applied to tumors containing either or both of the following: (1) 10 or more solid cancer nests in the microscopic field of a 4x objective lens and (2) a mucin-producing component fully occupied the microscopic field of a 40x objective lens. Regarding G3, vascular invasion, and tumor budding as indicating the risk of metastasis, nodal involvement rate was 21.0% in the tumors with 1 or more risk factors, whereas it was only 1.7% in the no-risk tumors (P < .0001). In patients treated with local excision only, nodal recurrence occurred in 3 (20%) of 15 risk-positive patients, whereas none of 42 patients without risk factors had nodal recurrence (P = .016). In cases of locally excised T1 CRC, G3 as determined by the proposed criteria, vascular invasion, and budding would comprise a useful combination of parameters for determining the indication for additional laparotomy.

Size does not determine the grade of malignancy of early invasive colorectal cancer

To clarify the clinicopathological characteristics of small and large early invasive colorectal cancers (EI-CRCs), and to determine whether malignancy grade depends on size. A total of 583 consecutive EI-CRCs treated by endoscopic mucosal resection or surgery at the National Cancer Center Hospital between 1980 and 2004 were enrolled in this study. Lesions were classified into two groups based on size: small (<or= 10 mm) and large (> 10 mm). Clinicopathological features, incidence of lymph node metastasis (LNM) and risk factors for LNM, such as depth of invasion, lymphovascular invasion (LVI) and poorly differentiated adenocarcinoma (PDA) were analyzed in all resected specimens. There were 120 (21%) small and 463 (79%) large lesions. Histopathological analysis of the small lesion group revealed submucosal deep cancer (sm: >or= 1000 microm) in 90 (75%) cases, LVI in 26 (22%) cases, and PDA in 12 (10%) cases. Similarly, the large lesion group exhibited submucosal deep cancer in 380 (82%) cases, LVI in 125 (27%) cases, and PDA in 79 (17%) cases. The rate of LNM was 11.2% and 12.1% in the small and large lesion groups, respectively. Small EI-CRC demonstrated the same aggressiveness and malignant potential as large cancer.

Outcome of Endoscopic Resection for Early Invasive Colorectal Cancer Based on the Tumor Recurrence

Outcome of Endoscopic Resection for Early Invasive Colorectal Cancer Based on the Tumor Recurrence

大腸ｓｍ癌の臨床病理学的検討と治療方針

1970年より1995年まで, 当科で経験した大腸sm癌は202例であり, 内訳は男性139人, 女性63人で平均年齢は60.0±12.0歳であった.平均腫瘍最大径は20.3±13.9mmであり, 腫瘍形態は隆起型140例 (69.3%), 表面型62例 (30.7%) であった.腫瘍占居部位はS状結腸と直腸で163例 (80.7%) であった.リンパ節転移は202例中10例 (4.9%) に認め, 脈管侵襲, 深達度, 占居部位, 形態がリンパ節転移のリスクファクターとなっていた.IsやIIa+IIcはsm高度浸潤の確率が高く (92.0%, 90.0%), 初回治療より根治的手術を選択するのが妥当であると考えられた.さらに郭清範囲は, n2以上の転移は当科では経験しておらず原則としてD1+αで十分と考えられた.

Management of early invasive colorectal cancer. Risk of recurrence and clinical guidelines.

The purpose of this study was the evaluation of various factors in the formulation of guidelines for treatment of early invasive colorectal cancer, in which malignant cells extend through the muscularis mucosa into the submucosa but do not deeply invade the muscularis propria. A total of 182 patients were followed for at least five years or until death, with early invasive cancer diagnosed between 1982 and 1989. Patients were grouped according to the level of invasion, as follows: 64 patients with slight carcinoma invasion of the muscularis mucosa (200-300 microns; sm1), 82 with intermediate invasion (sm2), and 36 with carcinoma invasion extending to the inner surface of the muscularis propria (sm3). The configuration, diameter, and histologic grade of adenocarcinoma and lymphovascular invasion were correlated with level of invasion. After endoscopic polypectomy or local resection, 4 patients showed local recurrence and 13 patients showed lymph node metastasis. None of these 17 patients had sm1 disease. The level of invasion, configuration, and location were significant risk factors for development of lymph node metastasis or local recurrence (P < 0.05), but lymphovascular invasion, histologic grade, and diameter were not risk factors. Preoperative assessment of the level of invasion using this classification, in which the submucosa is divided into three depths, may decrease the incidence of unnecessary surgery for sessile polyps. Assessment according to the level of invasion is useful in the formulation of appropriate guidelines for the treatment of early invasive cancer.