International consensus guidelines for scoring the histopathological growth patterns of liver metastasis

Background:Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.Methods:Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.Results:Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).Conclusions:The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.

[1]  A. Nicholson,et al.  Angiogenesis in primary lung cancer and lung secondaries. , 1996, European journal of cancer.

[2]  I. Christensen,et al.  Histopathological Growth Pattern, Proteolysis and Angiogenesis in Chemonaive Patients Resected for Multiple Colorectal Liver Metastases , 2012, Journal of oncology.

[3]  S. Hirohashi,et al.  Fibrous pseudocapsule of metastatic liver tumors from colorectal carcinoma , 2000, Cancer.

[4]  C. Colpaert,et al.  Cutaneous breast cancer deposits show distinct growth patterns with different degrees of angiogenesis, hypoxia and fibrin deposition , 2003, Histopathology.

[5]  B. Döme,et al.  A Novel Concept of Glomeruloid Body Formation in Experimental Cerebral Metastases , 2003, Journal of neuropathology and experimental neurology.

[6]  H. Kemperman,et al.  αV Integrins on HT-29 Colon Carcinoma Cells: Adhesion to Fibronectin Is Mediated Solely by Small Amounts of αVβ6, and αVβ5 Is Codistributed with Actin Fibers , 1997 .

[7]  Michael Simons,et al.  Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis , 2013, Nature.

[8]  S. French,et al.  Metastatic patterns of cancers: results from a large autopsy study. , 2009, Archives of pathology & laboratory medicine.

[9]  Frank Winkler,et al.  Invasion patterns in brain metastases of solid cancers. , 2013, Neuro-oncology.

[10]  J. Jass,et al.  A NEW PROGNOSTIC CLASSIFICATION OF RECTAL CANCER , 1987, The Lancet.

[11]  D. Schuppan,et al.  Evolving therapies for liver fibrosis. , 2013, The Journal of clinical investigation.

[12]  E. van Marck,et al.  Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia , 2001, The Journal of pathology.

[13]  G. G. Van den Eynden,et al.  The histological growth pattern of colorectal cancer liver metastases has prognostic value , 2012, Clinical & Experimental Metastasis.

[14]  M. Choti,et al.  Urgent need for a new staging system in advanced colorectal cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  M. Kris,et al.  Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis , 2014, Cell.

[16]  H. Kemperman,et al.  alphaV Integrins on HT-29 colon carcinoma cells: adhesion to fibronectin is mediated solely by small amounts of alphaVbeta6, and alphaVbeta5 is codistributed with actin fibers. , 1997, Experimental cell research.

[17]  I. Christensen,et al.  Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy , 2015, Cancer Microenvironment.

[18]  E. van Marck,et al.  Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia , 2004, British Journal of Cancer.

[19]  F. Lemaigre,et al.  Organogenesis and development of the liver. , 2010, Developmental cell.

[20]  M. Westphal,et al.  Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. , 2000, Neoplasia.

[21]  B. Vainer,et al.  The morphological growth patterns of colorectal liver metastases are prognostic for overall survival , 2014, Modern Pathology.

[22]  G. G. Van den Eynden,et al.  The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. , 2013, Cancer research.

[23]  J. Tímár,et al.  Mechanism of tumour vascularization in experimental lung metastases , 2015, The Journal of pathology.

[24]  Pieter Wesseling,et al.  Antiangiogenic Therapy of Cerebral Melanoma Metastases Results in Sustained Tumor Progression via Vessel Co-Option , 2004, Clinical Cancer Research.

[25]  F. Bierring,et al.  CELLULAR CHANGES IN THE VICINITY OF METASTATIC CARCINOMA, OBSERVED BY LIGHT AND ELECTRON MICROSCOPY. , 1964, Oncologia.

[26]  R. Labianca,et al.  ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[27]  D. Reisman,et al.  Rapid liver enlargement and hepatic failure secondary to radiographic occult tumor invasion: two case reports and review of the literature , 2012, Journal of Medical Case Reports.

[28]  E. Mello,et al.  Tumor growth pattern as predictor of colorectal liver metastasis recurrence. , 2014, American journal of surgery.

[29]  B. Nielsen,et al.  Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor‐1 in colon cancer liver metastases , 2009, International journal of cancer.

[30]  R. Semelka,et al.  Perilesional enhancement of hepatic metastases: correlation between MR imaging and histopathologic findings-initial observations. , 2000, Radiology.

[31]  L H Blumgart,et al.  Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. , 1999, Annals of surgery.

[32]  R. Lunevicius,et al.  Clinicopathological significance of fibrotic capsule formation around liver metastasis from colorectal cancer , 2001, Journal of Cancer Research and Clinical Oncology.

[33]  R. Palmqvist,et al.  Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour. , 2012, Anticancer research.

[34]  Csaba Bödör,et al.  Structural analysis of oval‐cell–mediated liver regeneration in rats , 2012, Hepatology.

[35]  E. van Marck,et al.  Two distinct expression patterns of urokinase, urokinase receptor and plasminogen activator inhibitor‐1 in colon cancer liver metastases , 2009, International Journal of Cancer.

[36]  Zev Rosenwaks,et al.  Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration , 2010, Nature.

[37]  J. Rossant,et al.  Liver Organogenesis Promoted by Endothelial Cells Prior to Vascular Function , 2001, Science.

[38]  D. Jayne,et al.  The influence of invasive growth pattern and microvessel density on prognosis in colorectal cancer and colorectal liver metastases , 2007, British Journal of Cancer.

[39]  R. Jain,et al.  Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. , 2015, Journal of the National Cancer Institute.

[40]  G. Yousef,et al.  Co-option of Liver Vessels and Not Sprouting Angiogenesis Drives Acquired Sorafenib Resistance in Hepatocellular Carcinoma , 2016, Journal of the National Cancer Institute.

[41]  B. Döme,et al.  Lack of Angiogenesis in Experimental Brain Metastases , 2011, Journal of neuropathology and experimental neurology.

[42]  N. Sibson,et al.  The Vascular Basement Membrane as “Soil” in Brain Metastasis , 2009, PloS one.

[43]  G. G. Van den Eynden,et al.  Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases , 2016, Nature Medicine.

[44]  S. Love,et al.  ‘Revertant’ DCIS in human axillary breast carcinoma metastases , 1997, The Journal of pathology.

[45]  L. Rubbia‐Brandt,et al.  Dangerous halo after neoadjuvant chemotherapy and two‐step hepatectomy for colorectal liver metastases , 2009, The British journal of surgery.

[46]  K. Allison,et al.  Radiographically occult, diffuse intrasinusoidal hepatic metastases from primary breast carcinomas: a clinicopathologic study of 3 autopsy cases. , 2004, Archives of pathology & laboratory medicine.

[47]  I. Jonassen,et al.  Angiogenesis-independent tumor growth mediated by stem-like cancer cells , 2006, Proceedings of the National Academy of Sciences.

[48]  J. Larkin,et al.  Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models , 2016, The Journal of pathology.

[49]  M. Oertel,et al.  Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. , 2006, Gastroenterology.

[50]  E. van Marck,et al.  Lack of angiogenesis in lymph node metastases of carcinomas is growth pattern‐dependent , 2002, Histopathology.

[51]  K. Naresh,et al.  Angiogenesis is redundant for tumour growth in lymph node metastases , 2001, Histopathology.

[52]  G. Poston.  Staging of advanced colorectal cancer. , 2008, Surgical oncology clinics of North America.

[53]  M Buyse,et al.  Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis. , 1997, The American journal of pathology.

[54]  H. Hamperl.  Die Morphologie der Tumoren , 1956 .