Poorly Differentiated Clusters Grade Research Articles

Poorly differentiated clusters in colorectal cancer: a current review and implications for future practice.

Poorly differentiated clusters (PDC), defined as small groups of ≥5 tumour cells without glandular differentiation, have gained recent attention as a promising prognostic factor in colorectal cancer (CRC). Numerous studies have shown PDC to be significantly associated with other adverse histopathological features and worse clinical outcomes. PDC may hold particular promise in stage II colon cancer, where risk stratification plays a critical role in patient selection for adjuvant chemotherapy. In addition, emerging evidence suggests that PDC can predict lymph node metastasis in endoscopically resected pT1 CRC, potentially helping the selection of patients for oncological resection. In 'head-to-head' comparisons, PDC grade has consistently outperformed conventional histological grading systems both in terms of risk stratification and reproducibility. With a number of large-scale studies now available, this review evaluates the evidence regarding the prognostic significance of PDC, considers its relationship with other emerging invasive front prognostic markers (such as tumour budding and stroma type), assesses its 'practice readiness', addressing issues such as interobserver reproducibility, scoring methodologies and special histological subtypes (e.g. micropapillary and mucinous carcinoma), and draws attention to ongoing challenges and areas in need of further study. Finally, emerging data on the role of PDC in non-colorectal cancers are briefly considered.

The presence of poorly differentiated clusters predicts survival in stage II colorectal cancer.

In stage II colorectal carcinoma (CRC), adjuvant chemotherapy is reserved to cases at high risk of adverse outcome. This study aims to investigate the prognostic value of tumor budding (TB) and poorly differentiated clusters (PDC) in this setting. In a cohort of 149 patients with surgically resected stage II CRC not undergoing neoadjuvant or adjuvant treatments, we assessed the prognostic value of several clinical-pathological variables, including PDC and TB, on cancer-specific survival (CSS). Rectal location, lymphovascular invasion, and a number of lymph nodes < 12 confirmed to be significant and independent predictors of shorter CSS. A total of 117 CRCs were graded as PDC-G1 (0-4 PDCs), 19 as PDC-G2 (5-9 PDCs), and 13 as PDC-G3 (> 9 PDCs). Ninety-eight cases had PDC absent. TB foci were found in 91 CRCs; 121 were classified Bd1, 16 were Bd2, and 12 were Bd3. PDC-G2/G3 was significantly prognostic of shorter CSS (P< 0.0001). Among PDC-G1 cases, the presence of PDC was significantly associated with reduced CSS (P< 0.0001). Moreover, in the whole 149 CRCs, it had higher sensitivity and specificity to identify high-risk patients, compared to PDC grade, and it was independently associated with shorter CSS at multivariate analysis. High TB grade (Bd3) was significantly associated with shorter CSS (P= 0.0001), but it lost prognostic value at multivariate analysis. These findings suggest that the presence of PDC in stage II CRCs might be added to the pool of high-risk factors, warranting the use of adjuvant chemotherapy.

Prognostic Value of Poorly Differentiated Clusters in Liver Metastatic Lesions of Colorectal Carcinoma.

Colorectal liver metastasis (CRLM) is the most common pattern of metastases or recurrence in colorectal carcinoma; however, no robust pathologic prognostic factors have been identified. This study aimed to verify the prognostic value of poorly differentiated clusters (PDC) in liver metastatic lesions and to clarify the correlation between PDC in liver metastatic lesions (PDC) and the primary tumor histology. Consecutive patients who underwent resection for CRLM were pathologically reviewed. PDC was defined as cancer clusters comprising ≥5 cancer cells and lacking glandular formation and was quantifiably graded as G1 (<5 clusters), G2 (5 to 9 clusters), and G3 (≥10 clusters) based on the highest number of clusters observed under ×20 magnification. The cohort comprised 204 patients. PDC was classified as G1, G2, and G3 for 68, 69, and 67 patients, respectively, and it was significantly associated with PDC grade in the primary tumor (P<0.001). Among the potential prognostic factors, tumor budding in the primary tumor, PDC in the primary tumor, the number of liver metastases, extrahepatic metastasis, and PDC significantly influenced overall survival (OS) after CRLM resection. According to the PDC grade, the 5-year OS rates were 68.9%, 48.3%, and 39.5% for G1, G2, and G3 (P<0.001), respectively. Multivariate analysis for OS showed that PDC grade, tumor budding in the primary tumor, the number of liver metastasis and extrahepatic metastasis were independent prognostic factors. In conclusion, there is a correlation in the PDC grade between the primary tumor and liver metastatic lesion, and PDC grade could be a promising new prognostic factor after CRLM resection.

Clinicopathological significance of heterogeneic ezrin expression in poorly differentiated clusters of colorectal cancers.

Multicellular structures, such as tumor buddings and poorly differentiated clusters (PDC), exist at the invasive front of colorectal cancers (CRC). Although it has been reported that CRC with PDC showed frequent lymph node metastases with a worse prognosis, the molecular markers of PDC that are responsible for prognosis have not been identified. We here noticed for the first time that Ezrin, a regulator of the actin cytoskeleton, is expressed in the corner cells of PDC. We then aimed to verify whether heterogeneous Ezrin expression in PDC predicts the prognosis of CRC patients. We immunohistochemically analyzed Ezrin expression in PDC of 184 patients with completely resected stages I‐III CRC. We established the Ezrin corner score (ECS), which quantifies the tendency of Ezrin‐positive cells to accumulate at the corners of PDC. On the basis of ECS values, 2 indices, the mean ECS and the number of PDC with high ECS, were obtained. Both indices were significantly higher in CRC with lymphatic invasion, higher PDC grade, and presence of micropapillary (MP) PDC. The mean ECS‐high group showed shorter recurrence‐free survival than the mean ECS‐low group but without significance. The other index, the number of ECS‐high PDC, was significantly associated with recurrence‐free survival. These results suggest that Ezrin is involved in PDC progression and lymphatic invasion, and that ECS may be a marker for aggressive PDC.

Clinicopathological significance of poorly differentiated clusters in colorectal adenocarcinoma

Objective: To investigate the correlation between poorly differentiated clusters (PDCs) in colorectal adenocarcinomas with clinicopathological parameters and its clinicopathological significance. Methods: One hundred and eighty-three colorectal adenocarcinomas resected by radical proctocolecomy were collected at Nanjing Hospital(Nanjing First Hospital), Nanjing Medical University, from January to December 2017. There were 122 male and 61 female patients with age ranging from 42 to 89 years (mean of 68 years). Tumor diameter ranged from 2 to 14 cm (mean 4.5 cm). There were 124 colon cancers and 59 rectal cancers. The number and grade of PDCs in the colorectal adenocarcinoma were evaluated by H-E staining. The overall peritumoural inflammatory reaction was also evaluated. The relationship between PDCs and tumor grades and clinicopathological features and overall peritumoural inflammatory reaction of colorectal adenocarcinoma was analyzed. Results: Of 183 cases of colorectal adenocarcinoma, PDCs were seen in 104 cases (56.8%), of which 36 cases (19.7%) were grade 1, 28 cases (15.3%) were grade 2, and 40 cases (21.9%) were grade 3. PDCs were positively correlated with lymph node metastasis, vascular invasion, degree of differentiation, depth of invasion, and pTNM staging(P<0.05). The detection rate of PDCs in colon cancer was higher than that of rectal cancer(P<0.05). PDCs was unrelated to age, gender, tumor size, and degree of overall peritumoural inflammatory reaction (P>0.05). Among clinicopathological parameters, the grade of PDCs was correlated with lymph node metastasis and vascular invasion (higher than those without lymph node metastasis and vascular invasion, P<0.05); There was a positive correlation between the grade of PDCs and age, tumor differentiation and pTNM staging(P<0.05), and no significant difference between the grade of PDCs and gender, tumor size, tumor location, and depth of invasion was seen (P>0.05). There was no correlation between the grade of PDCs and the degree of overall peritumoural inflammatory reaction (P>0.05). Conclusions: PDC is a histological feature that predicts the aggressiveness of colorectal adenocarcinoma. Evaluation of PDC grade can better predict the biological behavior of colorectal cancer and more accurately guide the treatment and evaluate prognosis.

Poorly differentiated clusters: prognostic significance in colorectal carcinomas immunohistochemistry images.

Colorectal cancer (CRC) remains a major public health burden worldwide, despite increased knowledge on its pathogenesis and advances in therapy. We aimed to evaluate a new histological grading system based on poorly differentiated clusters (PDCs) counting - the PDCs grade (PDCs-G), and its clinicopathological and prognostic significance, compared to the World Health Organisation (WHO) grading system (WHO grade). We reviewed 71 surgical resection specimens for CRC from the Emergency County Hospital "Pius Brînzeu" Timisoara. The cases were graded using the WHO grade and the PDCs-G, with further analysis of their association with the other recognised prognostic parameters. Using the WHO grade, 9% of the analysed cases were G1, 80% G2, 11% G3, and none of the tumours was graded G4, while in the PDCs-G 16% were G1, 45% G2, and 39% G3. In multivariate analysis PDCs-G was significantly associated with the American Joint Committee on Cancer stage of the disease (AJCC stage) (p = 0.0003), depth of invasion (pT) (p = 0.0084), nodal status (LNM) (p < 0.0001), lymphovascular invasion (LVI) (p < 0.0001), perineural invasion (PNI) (p < 0.0052), and tumour border configuration (p < 0.0001). The novel grading system based on PDCs counting is an additional histological tool in the evaluation of CRC and a promising new prognostic factor for these patients.

Poorly Differentiated Clusters Predict a Poor Prognosis for External Auditory Canal Carcinoma.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (< 5 cells), and laminin 5-γ2 staining of SCC of the EAC are associated with shorter survival. However, clusters composed of ≥ 5 tumor cells are also found in the stroma. Previous reports of colorectal cancer suggest that poorly differentiated clusters (PDCs) are a negative prognostic indicator. Here, we report on the association between PDCs and prognosis in SCC of the EAC. PDCs and tumor budding were histopathologically and immunohistochemically (cytokeratin AE1/AE3) analyzed in 31 cases of pre-treatment biopsy SCC of the EAC. Clusters in the stroma composed of < or ≥ 5 cancer cells were defined as tumor budding or PDCs, respectively. Entire tumors were initially scanned to identify greatest PDC density. Tumors with low or high PDC density were classified as low- and high-grade, respectively. Patients with high-grade PDCs had a significantly poorer outcome than those with low-grade. Even in cases of low-grade tumor budding, those with high-grade PDCs had a poor prognosis. Multivariate analysis results indicated that high-grade PDCs were associated with poor prognosis. PDC grade can provide a more accurate prognosis than tumor budding in SCC of the EAC.

Tumor budding and poorly-differentiated cluster in prognostication in Stage II colon cancer

Comparison between tumor budding (TB) and poorly-differentiated clusters (PDC) for prognostication in Stage II colon cancer was not extensively studied in literature. In this retrospective study, we assessed TB (according to the consensus statement in 2016) and PDC in 135 Stage II colon adenocarcinoma resection specimens. Counting of TB and PDC was performed on H&E slides. High-grade TB (Bd3 (≥10 tumor buds in 0.785 mm2)) and high-grade PDC (Grade 3 (≥10)) were found in 20% and 17% of cases respectively. High-grade TB was associated with pT4 (p = 0.008) and presence of lymphovascular invasion (p = 0.001). There was correlation between TB and PDC grades (p < 0.001), in which both grades were the same or one grade apart in majority of the cases (95%). Both TB and PDC correlated with 5-year disease-specific survival (DSS) and overall survival (OS) (DSS for TB: 89% (Bd1); 73% (Bd2); 52% (Bd3), p = 0.001) (DSS for PDC: 88% (Grade 1); 72% (Grade 2); 61% (Grade 3), p = 0.021). Survival curves of Stage II colon cancer could be further stratified by TB and PDC (log-rank tests: TB p < 0.001; PDC p = 0.009). Combining TB and PDC grades into single grading system (high-grade: Bd3 + G2, Bd2 + G3, Bd3 + G3; low-grade: other combinations) was found to have strong correlation with both 5-year DSS and OS (both p < 0.001). Our study has confirmed TB and PDC as independent prognostic factors in Stage II colon cancer, and might help selecting high-risk patients for adjuvant chemotherapy.

Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer.

Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.

Histological grading based on poorly differentiated clusters is predictive of tumour response and clinical outcome in rectal carcinoma treated with neoadjuvant chemoradiotherapy.

The clinical outcome of patients with locally advanced rectal cancer who undergo neoadjuvant chemoradiotherapy (CRT) is influenced by the tumour response to treatment, which is reflected by tumour regression grade and post-treatment (y) TNM stage. Little is known about the prognostic value of pretreatment histopathological features of the tumour that may be useful to discriminate potential non-responders and to design tailored therapeutic strategies. In this study, we aimed to investigate the prognostic role of poorly differentiated clusters (PDCs) of neoplastic cells in pretreatment biopsies of patients with rectal cancer treated with neoadjuvant CRT. Grading based on PDC counting was retrospectively applied to 204 pretreatment endoscopic biopsies of rectal carcinomas from patients treated with neoadjuvant CRT and surgery. Interobserver agreement in the assessment of PDC grade was good. High PDC grade was significantly associated with high yT stage (P=0.044), yM+ status (P=0.0004), and unchanged TNM stage or TNM upstaging (P=0.032). In addition, high PDC grade was a significant and independent prognostic factor for cancer-specific survival. PDC grade may be assessed in preoperative biopsies of rectal cancer with good reproducibility. High PDC grade in a pretreatment tumour is significantly associated with a poor response to therapy. Hence, we suggest that PDC grading might be used as a significant predictive and prognostic factor in patients with locally advanced rectal cancer who are treated with neoadjuvant CRT, and to identify high-risk patients who need surgery and adjuvant chemotherapy.

Poorly differentiated clusters as a prognostic marker at the invasive front of colon cancer.

621 Background: Histology at the invasive front of colon cancer can predict malignant potential. However, the optimal histological marker is yet to be established. This study compares the various invasive front histologic markers. Methods: A single-institution prospective database was queried for consecutive patients who underwent curative resection for Stage I-III colon adenocarcinoma from 2007-14. Histologic features were reviewed by a pathologist, including poorly differentiated clusters (PDC), tumor budding (BD), perineural invasion (PN), desmoplastic reaction (DR) and Crohn’s like reaction (CLR) at the invasive front, and WHO grade of the whole tumor. PDC was defined as cancer clusters of ≥ 5 cancer cells that lack a gland-like structure, and was graded into G1 ( &lt; 5), G2 (5-9) and G3 ( ≥ 10) by the highest number of the clusters /HPF. Clinical outcome included recurrence free survival (RFS) and peak hazard function of recurrence and death identified using the kernel-smoothing method. Predictive accuracy was measured with concordance probability estimate (CPE) for proportional hazards regression. Inter-observer agreement was assessed by weighted kappa values on diagnoses rendered by 3 pathologists on 50 randomly selected cases. Results: The study cohort consisted of 851 patients with a median follow up of 36 months. PDC, BD, PN, DR and CLR at the invasive front were significantly associated with RFS. When analyzed by stage, PDC, BD and PN were associated with RFS both in Stage II and Stage III, while the others were prognostic only in Stage III. CPE was the highest in PDC (0.642), indicating the best predictive accuracy, while it was the lowest in WHO grade (0.526). Weighted kappa was also the highest for PDC, indicating the best inter-observer agreement (PDC: 0.824, WHO grade: 0.568). The smoothed graph of the hazard function showed that the risk of recurrence was not only the highest but peaked earlier for PDC G3 (between0 and 12 months) than PDC G2 (between12 and 24 months) and G1 (no evident peak). Conclusions: Of the commonly evaluated histologic markers at the invasive front, PDC grade is the most predictive and reproducible. Further confirmatory investigations are warranted to determine if PDC can replace WHO grade.

Histologic prognostic markers in stage IIA colorectal cancer: a comparative study

Objective: pTNM stage IIA colorectal cancer (CRC) is not currently submitted to any adjuvant treatment due to its good prognosis. Nevertheless, a percentage of cases unexpectedly recur. The aim of this study was to assess and compare the prognostic value and inter-observer agreement of a novel histological grading system based on the counting of poorly differentiated clusters (PDC) of cancer cells and that of conventional histological grade, lymphatic, venous and perineural invasion (LVI, VI, PNI), tumour budding (TB) and tumor border configuration in stage IIA CRC.Materials and methods: the afore mentioned histological parameters were assessed in 82 stage IIA CRCs. Inter-observer agreement and correlation with tumour relapse were analyzed by using Fleiss–Cohen’s weighted K statistics, Fisher exact test and Chi-squared test. The Mantel–Cox log-rank test was applied to assess the strength of association with disease-free interval (DFI).Results: inter-observer agreement was very good/good in the assessment of PDC presence and grade, while it was moderate at best in the evaluation of the other parameters. The presence of PDC, high PDC grade, LVI and TB were significantly associated with disease progression (p < 0.0001; p = 0.0012; p = 0.0308; p = 0.0002) and shorter DFI (p = 0.0001; p < 0.0001; p = 0.0129; p = 0.0008). PDC presence (p < 0.0001) and TB (p = 0.012) were independent prognostic factors in multivariate analysis.Conclusions: our findings suggest that the assessment of PDC may be useful to stratify patients with stage IIA CRC for recurrence risk, and to identify high risk patients who could benefit from adjuvant chemotherapy.

KRAS, NRAS, BRAF mutations and high counts of poorly differentiated clusters of neoplastic cells in colorectal cancer: observational analysis of 175 cases

A novel grading system based on the counting of poorly differentiated clusters (PDC) of neoplastic cells at the invasive margin and in the tumour stroma was recently introduced among the histological parameters predictive of adverse clinical outcome in colorectal cancer (CRC). The aim of this study was to correlate the histological grade based on PDC and the mutational status of KRAS, NRAS and BRAF genes in 175 consecutive CRCs. The highest PDC count under the objective lens of a ×20 microscopic field in each tumour was considered for grading assessment, so that PDC counts <5, 5-9 and ≥10 PDCs were defined grade 1, grade 2 and grade 3, respectively. Hotspots mutations were identified using the MassArray platform. Overall, there were 42 (24%) mutated tumours. Mutational status was significantly associated with high pT stage (p = 0.0021), advanced pTNM stage (p = 0.0018), nodal metastases (p = 0.006), tumour budding (p = 0.022) and high PDC grade (p = 0.0022). KRAS mutations were significantly associated with PDC grade (p = 0.0379), while BRAF mutations were associated with PDC-G3 although statistical significance was not reached. No significant associations were found between NRAS and PDC. The significant association between mutated KRAS and PDC grade suggests that KRAS mutations may be involved in the formation of PDC.

Prognostic significance of grading based on the counting of poorly differentiated clusters in colorectal mucinous adenocarcinoma

Mucinous adenocarcinoma (MAC) of the colon and rectum is a histological entity with still indefinite prognostic significance. Although it was previously designated as poorly differentiated by convention, the most recent World Health Organization guidelines indicate that the level of maturation of the epithelium determines differentiation in MAC and that microsatellite instability status should be taken into account for its histological grading. Nonetheless, precise criteria for grading are not provided, and the prognostic value of histological grading in MAC still remains unclear. In the present study we aimed to investigate the prognostic value of a grading system based on the counting of poorly differentiated clusters (PDC) of neoplastic cells in 108 colorectal MACs and to compare its reproducibility and significance with those of a grading system based on glandular differentiation. We found that PDC grade was more reproducible and significantly associated with disease progression (P = .0089) as well as with death from colorectal cancer (P = .0035) in our MACs, as compared to the grade based on glandular differentiation, which was not associated with any of the clinicopathologic variables. Moreover, PDC grade emerged as a significant, independent prognostic factor of recurrence-free survival (P = .0198) and cancer-specific survival (P = .0293) in MAC. Interestingly, the prognostic value of PDC grade was unaltered following incorporation of mismatch repair system status in grading. In conclusion, we demonstrated for the first time that PDC grading is feasible, reproducible, and prognostically relevant in MAC, which may support its use in routine practice.

Prognostic value of poorly differentiated clusters in the primary tumor in patients undergoing hepatectomy for colorectal liver metastasis

This study aimed to determine the prognostic value of a novel grading system based on the histologic assessment of poorly differentiated clusters (PDCs) in the primary lesions in patients with hepatectomy for colorectal liver metastasis (CRLM). Preoperative survival predictors for CRLM are required to determine candidates for perioperative chemotherapy who would otherwise have a poor prognosis. In total, 411 consecutive patients undergoing curative resection of primary colorectal cancers and metastatic liver lesions at 2 institutions were enrolled. Cancer clusters comprising ≥ 5 cancer cells, lacking a gland-like structure, were defined as PDCs and quantifiably graded. According to PDCs, 65, 127, and 219 patients were classified as being grades (G)1, G2, and G3, respectively. PDCs were associated with T and N stages and tumor budding in primary tumor, extrahepatic disease, and serum CEA levels (P ≤ .0001-.045), but not with the number and size of liver metastasis. PDC grade significantly influenced recurrence rate in extrahepatic sites, including the lung and peritoneum (P < .0001). The 2-year disease-free survival after hepatectomy was 64.6%, 38.8%, and 22.4% in G1, G2, and G3, respectively. Based on multivariate analysis, PDC grade was selected as an independent prognostic factor together with other conventional factors such as extrahepatic disease and the number of liver metastasis. PDC grade in primary lesions is a novel potent prognostic indicator in CRLM independent of the anatomic extent of disease. Notably, PDC grade can bias survival rates in clinical studies targeting perioperative chemotherapy in CRLM.

Impact of “poorly differentiated clusters” in primary lesion as a novel prognostic indicator in colorectal liver metastasis.

3625 Background: Preoperative predictors for survival are needed in colorectal liver metastasis in order to select poor-risk group that truly requires perioperative chemotherapy. This study aimed to elucidate survival predictors in patients undergoing curative hepatectomy for colorectal liver metastasis, particularly focusing on the impact of poorly differentiated clusters (PDC); a novel histologic grading system in primary lesion. Methods: A total of 424 consecutive patients undergoing curative resection of both primary colorectal cancers and metastatic liver lesions at two referral centers were enrolled in the study. Determinants of overall survival (OS) and recurrence free survival (RFS) after hepatectomy were investigated by univariate and multivariate analysis, using detailed clinicopathological parameters in primary and metastatic lesions. Cancer clusters of ≥5 cancer cells and lacking a gland-like structure were counted under a x20 objective lens in a field containing the highest number of clusters at invasive front of primary lesions, and tumors with &lt;5, 5 to 9, and ≥10 clusters were classified as PDC grade (G)1, G2 and G3, respectively (n=65, 132, and 227 tumors, respectively). Results: OS and RFS at 3 years were 59% and 27%, respectively, with average follow up period of 43 months. PDC grade in primary lesion was strongly associated with both 3-year-OS (83%, 62%, and 51%, respectively, p&lt;0.0001) and 3-year-RFS (55%, 30%, and 17%, respectively, p&lt;0.0001). Multivariate analysis revealed that PDC grade in primary lesion was the most potent prognostic factor after hepatectomy independent of T and N of primary lesion and size of liver metastasis. Conclusions: PDC grade in primary lesion is a novel potent prognostic indicator in colorectal liver metastasis, which is independent of T and N. It is noteworthy that PDC grade can bias the survival in clinical studies targeting perioperative chemotherapy in colorectal liver metastasis.