Histopathological Growth Patterns Research Articles

Artificial intelligence in the diagnosis and management of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the third most common malignancy worldwide, with approximately 50% of patients developing colorectal cancer liver metastasis (CRLM) during the follow-up period. Management of CRLM is best achieved via a multidisciplinary approach and the diagnostic and therapeutic decision-making process is complex. In order to optimize patients’ survival and quality of life, there are several unsolved challenges which must be overcome. These primarily include a timely diagnosis and the identification of reliable prognostic factors. Furthermore, to allow optimal treatment options, a precision-medicine, personalized approach is required. The widespread digitalization of healthcare generates a vast amount of data and together with accessible high-performance computing, artificial intelligence (AI) technologies can be applied. By increasing diagnostic accuracy, reducing timings and costs, the application of AI could help mitigate the current shortcomings in CRLM management. In this review we explore the available evidence of the possible role of AI in all phases of the CRLM natural history. Radiomics analysis and convolutional neural networks (CNN) which combine computed tomography (CT) images with clinical data have been developed to predict CRLM development in CRC patients. AI models have also proven themselves to perform similarly or better than expert radiologists in detecting CRLM on CT and magnetic resonance scans or identifying them from the noninvasive analysis of patients’ exhaled air. The application of AI and machine learning (ML) in diagnosing CRLM has also been extended to histopathological examination in order to rapidly and accurately identify CRLM tissue and its different histopathological growth patterns. ML and CNN have shown good accuracy in predicting response to chemotherapy, early local tumor progression after ablation treatment, and patient survival after surgical treatment or chemotherapy. Despite the initial enthusiasm and the accumulating evidence, AI technologies’ role in healthcare and CRLM management is not yet fully established. Its limitations mainly concern safety and the lack of regulation and ethical considerations. AI is unlikely to fully replace any human role but could be actively integrated to facilitate physicians in their everyday practice. Moving towards a personalized and evidence-based patient approach and management, further larger, prospective and rigorous studies evaluating AI technologies in patients at risk or affected by CRLM are needed.

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Histopathological Growth Patterns of Resected Non-colorectal, Non-neuroendocrine Liver Metastases: A Retrospective Multicenter Study

Introduction: Distinct Histopathological Growth Patterns (HGPs) can be identified in liver metastases originating from melanoma, breast- and colorectal cancer. HGPs are related to survival after resection. A desmoplastic HGP, characterized by a desmoplastic ring separating the tumour cells from the liver parenchyma, marks good prognosis for each of these tumours. Whether HGPs extend to other tumour types and can be considered a pan-cancer phenomenon remains unknown. This study evaluates the presence of HGPs and their prognostic value in non-colorectal, non-neuroendocrine liver metastases. Methods: A retrospective multicentre study was performed in patients who underwent curative-intent resection of non-colorectal, non-neuroendocrine liver metastasis. HGPs were classified as desmoplastic or non-desmoplastic on H&E slides according to consensus guidelines. Overall- (OS) and recurrence free (RFS) survival were evaluated using Kaplan-Meier and multivariable Cox regression analysis. Results: In total, 132 patients with liver metastasis from 25 tumour types (95 carcinoma, 9 sarcoma, 14 melanoma, 14 other) were considered eligible for analysis, of which 26 (20%) had a desmoplastic HGP. Five-year OS and RFS (95%CI) were 53% (36-78%) versus 40% (30-53%), and 33% (19-61%) versus 15% (9-27%) for desmoplastic compared to non-desmoplastic patients, respectively (p=0.031 & p=0.004, Figure 1). On multivariable analysis (HR [95%CI]) a desmoplastic HGP was prognostic for both OS (0.46 [0.25-0.86], p=0.01) and RFS (0.38 [0.21-0.69], p<0.01) (table 1). Conclusions: This study demonstrates that HGPs extend to a variety of liver metastatic tumours and suggests that the desmoplastic HGP is a pan-cancer biomarker for good survival after surgical resection of liver-metastasis. Figure. Tabled 1Table. Uni-and Multivariable Cox regression for OS and RFSOverall SurvivalUnivariatepMV (n=124)pProgression Free SurvivalUnivariatepMV (n=119)pChemotherapyReference-Reference-ChemotherapyReference-Reference-No ChemotherapyNo ChemotherapyNeoadjuvant0.90 [0.52-1.53]0.690.98 [0.56-1.74]0.96Neoadjuvant0.71 [0.43-1.15]0.160.75 [0.45-1.25]0.26Adjuvant3.93 [0.92-16.80]0.065.49 [1.18-25.46]0.03Adjuvant1.73 [0.41-7.27]0.452.83 [0.63-12.78]0.18Neoadjuvant and adjuvant1.16 [0.63-2.14]0.631.14 [0.59-2.18]0.7Neoadjuvant and adjuvant1.17 [0.68-2.02]0.561.31 [0.73-2.35]0.37Nr. LM (multiple)1.44 [0.89-2.31]0.141.33 [0.80-2.21]0.27Nr. LM (Multiple)1.34 [0.87-2.09]0.191.25 [0.77-2.01]0.36Adam Score1.15 [0.98-1.35]0.091.21 [1.04-1.42]0.02Adam Score1.15 [0.99-1.35]0.071.27 [1.08-1.48]<0.01HGP (Non-desmoplastic)0.52 [0.28-0.95]0.030.51 [0.27-0.95]0.04HGP (Non-desmoplastic)0.44 [0.25-0.78]<0.010.38 [0.21-0.71]<0.01 Open table in a new tab

Primary Colorectal Cancer Histopathology Predicts the Histopathological Growth Pattern of Corresponding Liver Metastasis

Introduction: Histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in the surgical management of colorectal cancer liver metastasis (CRLM); the desmoplastic HGP marks good prognosis whereas the non-desmoplastic HGP predicts favourable chemotherapy response. Clinical applicability is however limited as determination requires resection. This study investigates whether primary colorectal cancer (CRC) histopathology may predict the HGP of corresponding CRLM. Method: A retrospective cohort study was performed in treatment-naive patients undergoing CRLM resection. Thirteen distinct histopathology features were determined on H&E sections of resected CRC and compared between desmoplastic and non-desmoplastic CRLM; tumour sidedness, pT & pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. A point-based score (table) was calculated, assigning a point for each unfavourable feature. Multivariable logistic regression was performed using this score and TIL density as predictors. Results: 180 patients were included, of which 150 (83%) had non-desmoplastic CRLM. Unfavourable histopathology was more frequent in non-desmoplastic CRLM for all individual CRC features evaluated (figure), and significantly so for a lower TIL density and a “non-mature” stroma (both p<0.03). This was confirmed by the point-based score, which revealed a significant association between unfavourable CRC histopathology and non-desmoplastic CRLM (median [IQR]: 4 [2;5] vs 1 [1;3] unfavourable features, p<0.001). Multivariable logistic regression achieved good discriminatory performance to predict the HGP (AUC=0.74). Conclusions: The current study observes an association in treatment-naive patients between CRC histopathology and the HGP of corresponding CRLM.Tabled 1CRC histopathology featurePointsCRC histopathology featurePointsRight-sided tumour+1Perineural invasion+1Poorly differentuiated+1(Lympho-)vascular invasion+1pT4 tumour+1Extramural venous invasion+1Positive lymph node(s)+1Peritumoural buddig (II or III)+1Tumour deposit(s)+1Non-mature stroma type+1Absent Chron's-like lymphoid reaction+1Infiltrative CRC growth pattern+1 Open table in a new tab

The Presence of Vessel Co-option Determines Overall Survival in Patients with Colorectal Cancer Liver Metastasis

Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis with an overall 5-year survival rate of 5-10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly different rates of patient survival, and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden, and pattern of cancer progression in light of their HGP’s, and to consider their potential effect on surgical decision making. Methods: We performed a retrospective multivariant analysis on clinical data from patients with CRCLM (n=275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. Results: 107 patients (43.7%) were angiogenic and 138 patients (56.3%) were vessel co-opting. The 3 and 5-year survival rates for angiogenic patients compared to vessel co-opting patients were 54% and 34.6% vs 47.1% and 13% respectively (p<0.0001). Multivariate analysis showed patients with vessel co-opting CRCLM had a higher incidence of extrahepatic metastatic disease (p=0.0215) compared to angiogenic CRCLM. Additionally, KRAS mutation status was a marker of an increased likelihood of disease recurrence (p=0.0434) as was increased number of liver tumors (p=0.0071) and multiple sites of extrahepatic metastatic disease (p<0.0001). Conclusions: Multivariate analysis identified key clinical features correlating to the two HGPs. Determining liver tumor HGPs is essential for patient prognostication and treatment optimization.

Differentiation of histopathological growth patterns of colorectal liver metastases by MRI features.

It is necessary to develop an accurate non-invasive method to determine the histopathological growth pattern (HGP) of colorectal liver metastasis (CRLM) before surgery. The present study aimed to identify various HGPs of CRLM by magnetic resonance imaging (MRI) features. This retrospective study included 53 chemo-naïve patients with CRLM between December 2013 and September 2019. The HGPs of CRLM were assessed according to the international consensus guidelines, and were classified as either replacement HGP (rHGP) or non-rHGP. The MRI features of CRLM were retrospectively reviewed in consensus by two radiologists. The differences of MRI features between rHGP and non-rHGP tumors were compared by using Chi-square test and Student's t-test. The Spearman or Pearson correlation analysis was performed to determine the correlation between different MRI features. A receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic ability. Of the 53 chemo-naïve patients (mean age, 60.11±9.85 years; age range, 38-86 years), 12 were diagnosed as rHGP, while 41 were diagnosed as non-rHGP. Rim enhancement were more common in rHGP than in non-rHGP (P<0.001). Besides, the diameter difference (ΔD) between the precontrast and postcontrast images of rHGP was significantly larger than that of the non-rHGP (P=0.001). The rim width was correlated with ΔD, but not correlated with tumor size. The non-rHGP colorectal liver metastases were prone to be washed out in the delayed phases (P=0.043). The area under the curve (AUC) for the differentiation of rHGP and non-rHGP by using rim enhancement and ΔD was 0.828 (95% CI: 0.708-0.949). The MRI features of CRLM are characteristic and could help to differentiate rHGP and non-rHGP.

Treatment Strategies for Recurrent Colorectal Cancer Liver Metastasis in Light of Tumor Histopathologic Growth Patterns

Introduction: Two distinct histopathological growth patterns (HGPs) of colorectal liver metastases are known to have different rates of surgical margin involvement following resection, to respond differently to the standard of care treatment, and to have different prognostic features. In this project we analyzed patients who underwent 3-5 liver resections for colorectal liver metastases, to identify how HGP influenced surgical decision making and outcome.

Volumetric Based Quantification of Histopathological Growth Patterns Is Most Predictive of Progression Free Survival Following Resection of Colorectal Liver Metastases

Introduction: In colorectal liver metastases (CRCLM), the desmoplastic histopathological growth pattern (dHGP) is known to be a predictor of improved survival and surgical outcome compared with the replacement histopathological growth pattern (rHGP). Traditionally, HGP’s are determined separately for each lesion (i.e.- a lesion with more than 50% dHGP would be considered a desmoplastic lesion). We hypothesized that looking at the total volume of dHGP in the liver (disregarding dispersion between lesions) would be more predictive of progression free survival (PFS). Methods: We analyzed a prospectively maintained database of consecutive patients undergoing hepatectomy for CRCLM between 2009-2020. The volumes of colorectal liver metastases were calculated using the Philips CT liver analysis application. The results were matched with pathological reports, and the total volume of desmoplastic HGP were determined. PFS was analyzed based on percent of dHGP using multivariate linear regression. The predictive accuracy of volumetric-based histopathological-categorization of CRCLM was compared to the traditional method using forward model selection. Results: 54 patient who had full volumetric data available were included. Mean age was 63.0 years. Multivariate regression analysis demonstrated that for every 10% increase in relative total volume of dHGP there was a 2 month increase in PFS (p=0.005). Using model selection the volumetric HGP categorization method was found to be a better predictor of PFS compared to the traditional cutoff based methods. Conclusions: In our study, the total volume of desmoplastic HGP was a preferable predictor of progression free survival following liver resection for CRCLM, compared with traditionally used methods.

Different pulmonary adenocarcinoma growth patterns significantly affect survival

ObjectiveAdenocarcinoma (AC) is the number one pathological entity of lung cancer with approximately 30–40% of cases. It is known to be heterogeneous and has 5 histopathological growth patterns. We evaluated the long-term survival rates of patients with predominant subtypes. Methods290 patients with AC underwent pulmonary resection between 2012 and 2017 at our institution. We excluded all patients with lymph node involvement and distant metastases. Hence, 163 patients were included for further analysis. Predominant growth pattern was defined if more than 10% of cells showed a growth pattern. 1, 3, and 5-year survival rates were evaluated. Survival was assessed by Kaplan-Meier curves and the Cox proportional hazards model was used to identify prognostic factors for overall survival. ResultsPredominant growth patterns >10% were compared to <10% growth patterns of the same subtype. 1-year, 3-year, and 5-year overall survival rates of patients with predominant solid tumor growth >10% differed significantly from patients with <10% (88.4% vs. 97.6%, p = 0.04; 65.8% vs. 87.4% p = 0.001, 36.4% vs. 65.9% p = 0.01). Survival rates did not differ between >10% papillary and acinar growth compared to <10%. Kaplan-Meier curves showed reduced overall survival for patients with solid tumor growth >10% (log-rank 0.002). Solid tumor growth >10% was an independent prognostic factor for worse long-term survival (Hazard ratio: 3.05, p = 0.01). ConclusionOur study demonstrates that the presence of a predominant solid pattern in pulmonary adenocarcinoma is a factor for an unfavorable prognosis. This should be kept in mind in daily clinical practice.

Treatment of Early-Stage Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Subgroup Analysis of the Randomized German Hodgkin Study Group HD16 Study

Background:Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma entity accounting for approximately 5% of all Hodgkin lymphoma (HL) cases. Pathological and clinical characteristics differ from classical HL (cHL). In contrast to cHL, the malignant cells in NLPHL are consistently positive for CD20 but stain negative for CD30. The clinical course of NLPHL is usually indolent and patients present with early-stage disease more frequently than in cHL.Patients and Methods:We investigated characteristics and outcomes of 85 patients with NLPHL (stage IB and stage II without risk factors) who had treatment within the randomized German Hodgkin Study Group HD16 study for early-stage HL. Results were compared to those from 495 cHL patients (stage IB and stage II without risk factors) treated within the same study. Patients were randomized between standard treatment consisting of 2 cycles of ABVD followed by consolidation radiotherapy and treatment guided by interim positron emission tomography after 2 cycles of ABVD (PET-2). PET-2-guided treatment consisted of 2 cycles of ABVD alone for patients with a negative PET-2 and 2 cycles of ABVD followed by consolidation radiotherapy for patients with a positive PET-2 (defined as a Deauville score ≥ 3). Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method including 95%-confidence intervals (95%-CI) and hazard ratios (HR) obtained from Cox regression models. Analyses were performed descriptively.Results:Overall, 62/85 NLPHL patients (73%) were male as compared to 254/495 cHL patients (51%) (p=0.0002). The median age was 37 years (range: 19-71 years) among patients with NLPHL and 36 years (range: 18-75 years) among patients with cHL (p=0.4380). Information on the histopathological growth pattern was available for 67/85 NLPHL patients of which 44 (66%) had a typical growth pattern. The PET-2 was positive in 39/85 NLPHL patients (46%) and in 171/495 cHL patients (35%) (p=0.0507). After a median observation time of 64 months, the 5-year PFS was 90.3% (95%-CI: 83.8-96.7%) for all 85 NLPHL patients and 90.8% (95%-CI: 88.1-93.5%) for all 495 cHL patients (HR=1.1; 95%-CI: 0.5-2.1). The 5-year PFS rates for PET-2-positive NLPHL (n=39) and cHL (n=171) patients were 89.3% (95%-CI: 79.4-99.2%) and 91.6% (95%-CI: 87.2-96%) (HR= 1.3; 95%-CI: 0.5-3.5), respectively. The 5-year PFS rates for PET-2-negative NLPHL (n=46) and cHL (n=324) patients were 91% (95%-CI: 82.7-99.4%) and 90.4% (95%-CI: 87-99.4%) (HR=0.85; 95%-CI: 0.3-2.4), respectively. PET-2-negative NLPHL (n=25) and cHL (n=152) patients treated with 2 cycles of ABVD alone had 5-year PFS rates of 83% (95%-CI: 67.8-98.2%) and 88.2% (95%-CI: 82.7-93.6%) (HR=1.5, 95%-CI: 0.5-4.5), respectively. In contrast, PET-2-negative NLPHL (n=21) and cHL (n=172) patients treated with 2 cycles of ABVD followed by consolidation radiotherapy had 5-year PFS rates of 100% and 92.3% (95%-CI: 88.1-96.5%) (HR=0; 95%-CI: 0), respectively. NLPHL patients with a typical growth pattern (n=44) had a 5-year PFS of 95.2% (95%-CI: 88.8-100%) whereas patients with an atypical growth pattern (n=23) had a 5-year PFS of 82.2% (95%-CI: 66.3-98%) (HR=2.5; 95%-CI: 0.5-11.2). A total of 9 NLPHL patients experienced disease progression or relapse during follow-up. The median time to NLPHL recurrence was 14 months (range: 1-89 months). There were 2 cases of second primary malignancies (1 case of malignant melanoma, 1 case of stomach cancer) among patients with NLPHL. No patient developed histological transformation into aggressive B-cell non-Hodgkin lymphoma. The 5-year OS rates were 100% and 98.6% (95%-CI: 97.5-99.7%) (HR=0; 95%-CI: 0) for patients with NLPHL and cHL, respectively.Conclusion:Taken together, the 5-year outcomes for patients with newly diagnosed early-stage NLPHL were similar to their counterparts with cHL. Thus, the current standard of care for early-stage cHL consisting of 2 cycles of ABVD followed by consolidation radiotherapy represents a highly active option also for the treatment of patients with the initial diagnosis of stage IB and stage II NLPHL without risk factors. DisclosuresFuchs: Takeda: Consultancy, Honoraria; Lukon: Honoraria; Celgene: Honoraria; BMS: Honoraria; MSD: Honoraria. von Tresckow: AstraZeneca: Honoraria, Other: congress and travel support; Kite-Gilead: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Pentixafarm: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Engert: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Tessa Therapeutics: Consultancy; Amgen: Honoraria; ADC Therapeutics: Consultancy; MSD: Honoraria; Hexal: Honoraria.

The correlation between tumor thickness and aggressive histopathological pattern in Basal cell carcinoma

The significance of tumor thickness is not clear in the prognosis of basal cell carcinoma. We aimed to identify the relationship between the tumor thickness and aggressive histopathological growth pattern in BCC. We retrospectively reviewed 85 primary BCCs of 82 patients. A total of 78 (91.7%) tumor slides were available for review, 7 (8.2%) missing slides in archive could not to be re-evaluated. We recorded the histological subtype, ulceration, perineural invasion, and the tumor thickness. Tumors with infiltrative, micronodular, morpheaform and basosquamous features were classified as having an aggressive growth pattern. The aggressive growth pattern was determined in 21 (26.9%) tumors with a mean tumor thickness of 2.19±0.71mm (range, 0.9-3.40). The non-aggressive growth pattern was detected in 57 (73%) tumors and the mean tumor thickness was 1.76±0.87mm (range 0.50-4.40mm). There was a statistically significant difference in the mean tumor thickness between the tumors with aggressive growth pattern and non-aggressive growth pattern (p=0.033). Tumor thickness might have positive correlation with aggressive histological pattern. Measuring and reporting tumor thickness may be a more practical way to determine the pathological risk for BCC.

Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician’s and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker.

Histopathological growth patterns in patients with advanced nodular lymphocyte-predominant Hodgkin lymphoma treated within the randomized HD18 study: a report from the German Hodgkin Study Group.

We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49-1·47] and overall survival (HR = 0·85; 95% CI = 0·49-1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP.

Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFβ1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.

Radiomics diagnosed histopathological growth pattern in prediction of response and 1-year progression free survival for colorectal liver metastases patients treated with bevacizumab containing chemotherapy

ObjectiveTo investigate the capability of a radiomics model, which was designed to identify histopathologic growth pattern (HGP) of colorectal liver metastases (CRLMs) based on contrast-enhanced multidetector computed tomography (ceMDCT), to predict early response and 1-year progression free survival (PFS) in patients treated with bevacizumab-containing chemotherapy. MethodsPatients with unresectable CRLMs who were treated with bevacizumab-containing chemotherapy were included in this multicenter retrospective study. For each target lesion, the radiomics-diagnosed HGP (RAD_HGP) of desmoplastic (D) pattern or replacement (R) pattern was determined. Logistic regression and receiver operating characteristic (ROC) curves were used to assess lesion- and patient-based responses according to morphologic response criteria. One-year PFS was calculated using Kaplan-Meier curves. Hazard ratios for 1-year PFS were obtained through Cox proportional hazard regression analysis. ResultsAmong 119 study patients, 206 D pattern and 140 R pattern lesions were identified. In patients with multiple lesions, 52 had D pattern, 31 had R pattern, and 36 had mixed (D + R) pattern. The area under the curve value for RAD_HGP in predicting early response was 0.707 for lesion-based analysis and 0.720 for patient-based analysis. Patients with D pattern had a significantly longer PFS than patients with R pattern or mixed pattern (P < 0.001). RAD_HGP was the only independent predictor of 1-year PFS. ConclusionsHGP diagnosed using a radiomics model could be used as an effective predictor of PFS for patients with CRLMs treated with bevacizumab-containing chemotherapy.

Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.

Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases.

In modern anti-cancer therapy of metastatic colorectal cancer (mCRC) the anti-angiogenic treatment targeting sprouting angiogenesis is firmly established for more than a decade. However, its clinical benefits still remain limited. As liver metastases (LM) represent the most common metastatic site of colorectal cancer and affect approximately one-quarter of the patients diagnosed with this malignancy, its treatment is an essential aspect for patients' prognosis. Especially in the perioperative setting, the application of anti-angiogenic drugs represents a therapeutic option that may be used in case of high-risk or borderline resectable colorectal cancer liver metastases (CRCLM) in order to achieve secondary resectability. Regarding CRCLM, one reason for the limitations of anti-angiogenic treatment may be represented by vessel co-option (VCO), which is an alternative mechanism of blood supply that differs fundamentally from the well-known sprouting angiogenesis and occurs in a significant fraction of CRCLM. In this scenario, tumor cells hijack pre-existing mature vessels of the host organ independently from stimulating new vessels formation. This represents an escape mechanism from common anti-angiogenic anti-cancer treatments, as they primarily target the main trigger of sprouting angiogenesis, the vascular endothelial growth factor A. Moreover, the mechanism of blood supply in CRCLM can be deduced from their phenotypic histopathological growth pattern (HGP). For that, a specific guideline has already been implemented. These HGP vary not only regarding their blood supply, but also concerning their tumor microenvironment (TME), as notable differences in immune cell infiltration and desmoplastic reaction surrounding the CRCLM can be observed. The latter actually serves as one of the central criteria for the classification of the HGP. Regarding the clinically relevant effects of the HGP, it is still a topic of research whether the VCO-subgroup of CRCLM results in an impaired treatment response to anti-angiogenic treatment when compared to an angiogenic subgroup. However, it is well-proved, that VCO in CRCLM generally relates to an inferior survival compared to the angiogenic subgroup. Altogether the different types of blood supply result in a relevant influence on the patients' prognosis. This reinforces the need of an extended understanding of the underlying mechanisms of VCO in CRCLM with the aim to generate more comprehensive approaches which can target tumor vessels alternatively or even other components of the TME. This review aims to augment the current state of knowledge on VCO in CRCLM and other tumor entities and its impact on anti-angiogenic anti-cancer therapy.

Histopathological Growth Patterns and Survival After Resection of Colorectal Liver Metastasis: An External Validation Study.

BackgroundAfter resection of colorectal cancer liver metastases (CRLM), 2 main histopathological growth patterns can be observed: a desmoplastic and a nondesmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation.MethodsAn international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at 3 tertiary hospitals in the United States and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin and eosin–stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared with patients with a nondesmoplastic phenotype (any nondesmoplastic growth observed). Cutoff analyses on the extent of nondesmoplastic growth were performed. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided.ResultsIn total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% vs 3.6%, P = .01). Desmoplastic patients had superior 5-year OS (73.4%, 95% confidence interval [CI] = 64.1% to 84.0% vs 44.2%, 95% CI = 38.9% to 50.2%, P < .001) and DFS (32.0%, 95% CI = 22.9% to 44.7% vs 14.7%, 95% CI = 11.7% to 18.6%, P < .001) compared with their nondesmoplastic counterparts. A desmoplastic phenotype was associated with an adjusted hazard ratio for death of 0.36 (95% CI = 0.23 to 0.58) and 0.50 (95% CI = 0.37 to 0.66) for cancer recurrence. Prognosis was independent of KRAS and BRAF status. The cutoff analyses found no prognostic relationship between either OS or DFS and the extent of nondesmoplastic growth observed (all P > .1).ConclusionsThis external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of nondesmoplastic growth does not affect prognosis.

Value of histopathological growth pattern in predicting 3-year progression free survival after operation in patients with liver metastasis of colorectal cancer

Objectives: To investigate the value of histopathological growth patterns (HGP) in predicting the 3-year progression free survival (PFS) after resection the liver metastasis from patients with colorectal cancer. Methods: The clinicopathological data of the 111 patients with liver metastasis of colorectal cancer diagnosed at Peking University People's Hospital, Beijing, China from January 2007 to January 2017 were analyzed. After excluding the patients who did not meet the inclusion criteria, a total of 80 patients were analyzed. According to the international expert consensus on HGP, the HGP types of liver metastasis were evaluated. The correlation between HGP and other clinicopathological factors was analyzed using χ2 or Fisher test. Kaplan-Meier survival curve was used to examine 3-year PFS in the patients with liver metastasis of colorectal cancer by HGP. The independent risk factors of 3-year post-resection PFS were determined using univariable and multivariable analyses. Results: A total of 80 cases were analyzed, including 43 cases of desmoplastic type (54%), 32 cases of replacement type (40%), 3 cases of pushing type (4%), and 2 cases of mixed type (2%). There was no correlation of HGP with age, gender, time of metastasis, tumor burden, histological grade, mucous differentiation or microsatellite instability. The 3-year post-resection PFS of the patients with desmoplastic type was significantly longer than that of patients with replacement type. The univariable and multivariable analyses showed that HGP was an independent prognostic factor. Conclusions: The HGP of colorectal cancer metastases to the liver mainly present as desmoplastic and replacement types. HGP is an independent prognostic factor for the patients with liver metastasis of colorectal cancer after resection of the metastasis. Therefore, HGP should be clearly indicated in the pathological report to help guide clinical treatments.

Histopathological Growth Pattern of Colorectal Liver Metastases Impacts Local Recurrence Risk and the Adequate Width of Surgical Margin

Purpose: The histopathological growth pattern (HGP) of colorectal liver metastases (CLM) has been associated with prognosis. To elucidate if the HGP is associated with local recurrence risk and impacts the adequate width of surgical margin. Method: All consecutive patients resected for CLM in 2018-2019 were considered. HGP was prospectively classified as follows: desmoplastic, pushing and replacement. Surgical margin was classified as follows: R0 (margin ≥1 mm), R1vasc (0-mm margin, tumor detachment from intrahepatic vessels) and R1par (tumor exposure along transection plane). R0 resections were further distinguished in R0min (1-mm margin), and R0wide (>1-mm margin). Results: 340 resection areas in 136 patients were analyzed (70 R0min, 143 R0wide, 31 R1vasc, 96 R1par). HGP was desmoplastic in 26 cases, pushing in 221, and replacement in 93. Thirty-six local recurrences occurred (11%, median follow-up 21 months): 5 after R0, 3 after R1vasc, and 28 after R1par resections. In R1par group, local recurrence rate was high independently of the HGP (29%). In R1vasc and R0min groups, local recurrence risk was higher in the replacement group (29% vs 4% in pushing/desmoplastic group; 11% vs 4%). In R0wide group, local recurrence risk was low for all HGP (<1%). Independent predictors of local recurrence were replacement HGP (OR=3.246, P=0.021), R1par resection (OR=17.494, P<0.001), and CLM size (OR=1.020, P=0.041). Conclusion: Replacement HGP is associated with an increased risk of local recurrence. In these patients, a wide surgical margin should be pursued, since R1vasc and R0min resections could be insufficient. R1par resection is inadequate, independently of the HGP.