Skip to main content
Top
Published in: Clinical & Experimental Metastasis 4/2019

Open Access 01-08-2019 | Metastasis | Research Paper

Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy

Authors: D. J. Höppener, P. M. H. Nierop, E. Herpel, N. N. Rahbari, M. Doukas, P. B. Vermeulen, D. J. Grünhagen, C. Verhoef

Published in: Clinical & Experimental Metastasis | Issue 4/2019

Login to get access

Abstract

Colorectal liver metastases (CRLM) exhibit distinct histopathological growth patterns (HGPs) that are indicative of prognosis following surgical treatment. This study aims to assess the reliability and replicability of this histological biomarker. Within and between metastasis HGP concordance was analysed in patients who underwent surgery for CRLM. An independent cohort was used for external validation. Within metastasis concordance was assessed in CRLM with ≥ 2 tissue blocks. Similarly, concordance amongst multiple metastases was determined in patients with ≥ 2 resected CRLM. Diagnostic accuracy [expressed in area under the curve (AUC)] was compared by number of blocks and number of metastases scored. Interobserver agreement (Cohen’s k) compared to the gold standard was determined for a pathologist and a PhD candidate without experience in HGP assessment after one and two training sessions. Both the within (95%, n = 825) and the between metastasis (90%, n = 363) HGP concordance was high. These results could be replicated in the external validation cohort with a within and between metastasis concordance of 97% and 94%, respectively. Diagnostic accuracy improved when scoring 2 versus 1 blocks(s) or CRLM (AUC = 95.9 vs. 97.7 [p = 0.039] and AUC = 96.5 vs. 93.3 [p = 0.026], respectively), but not when scoring 3 versus 2 blocks or CRLM (both p > 0.2). After two training sessions the interobserver agreement for both the pathologist and the PhD candidate were excellent (k = 0.953 and k = 0.951, respectively). The histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy, making them a reliable and replicable histological biomarker.
Appendix
Available only for authorised users
Literature
1.
go back to reference Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefPubMed Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefPubMed
2.
go back to reference Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM (2006) Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 244:254–259CrossRefPubMedPubMedCentral Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM (2006) Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 244:254–259CrossRefPubMedPubMedCentral
3.
go back to reference Elferink MA, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JH (2015) Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands. Int J Colorectal Dis 30:205–212CrossRefPubMed Elferink MA, de Jong KP, Klaase JM, Siemerink EJ, de Wilt JH (2015) Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands. Int J Colorectal Dis 30:205–212CrossRefPubMed
4.
go back to reference van der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH (2015) Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 32:457–465CrossRefPubMed van der Geest LG, Lam-Boer J, Koopman M, Verhoef C, Elferink MA, de Wilt JH (2015) Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 32:457–465CrossRefPubMed
5.
go back to reference van der Stok EP, Spaander MCW, Grunhagen DJ, Verhoef C, Kuipers EJ (2017) Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol 14:297–315CrossRefPubMed van der Stok EP, Spaander MCW, Grunhagen DJ, Verhoef C, Kuipers EJ (2017) Surveillance after curative treatment for colorectal cancer. Nat Rev Clin Oncol 14:297–315CrossRefPubMed
6.
go back to reference Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS et al (2012) Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 4:283–301PubMedPubMedCentral Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS et al (2012) Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol 4:283–301PubMedPubMedCentral
7.
go back to reference Galjart B, van der Stok EP, Rothbarth J, Grunhagen DJ, Verhoef C (2016) Posttreatment surveillance in patients with prolonged disease-free survival after resection of colorectal liver metastasis. Ann Surg Oncol 23:3999–4007CrossRefPubMedPubMedCentral Galjart B, van der Stok EP, Rothbarth J, Grunhagen DJ, Verhoef C (2016) Posttreatment surveillance in patients with prolonged disease-free survival after resection of colorectal liver metastasis. Ann Surg Oncol 23:3999–4007CrossRefPubMedPubMedCentral
8.
go back to reference Ayez N, van der Stok EP, Grunhagen DJ, Rothbarth J, van Meerten E, Eggermont AM et al (2015) The use of neo-adjuvant chemotherapy in patients with resectable colorectal liver metastases: clinical risk score as possible discriminator. Eur J Surg Oncol 41:859–867CrossRefPubMed Ayez N, van der Stok EP, Grunhagen DJ, Rothbarth J, van Meerten E, Eggermont AM et al (2015) The use of neo-adjuvant chemotherapy in patients with resectable colorectal liver metastases: clinical risk score as possible discriminator. Eur J Surg Oncol 41:859–867CrossRefPubMed
9.
go back to reference van der Pool AE, Lalmahomed ZS, Ozbay Y, de Wilt JH, Eggermont AM, Jzermans JN et al (2010) ‘Staged’ liver resection in synchronous and metachronous colorectal hepatic metastases: differences in clinicopathological features and outcome. Colorectal Dis 12:e229–e235CrossRefPubMed van der Pool AE, Lalmahomed ZS, Ozbay Y, de Wilt JH, Eggermont AM, Jzermans JN et al (2010) ‘Staged’ liver resection in synchronous and metachronous colorectal hepatic metastases: differences in clinicopathological features and outcome. Colorectal Dis 12:e229–e235CrossRefPubMed
10.
go back to reference Lalmahomed ZS, Ayez N, van der Pool AE, Verheij J, IJzermans JN, Verhoef C (2011) Anatomical versus nonanatomical resection of colorectal liver metastases: is there a difference in surgical and oncological outcome? World J Surg 35:656–661CrossRefPubMed Lalmahomed ZS, Ayez N, van der Pool AE, Verheij J, IJzermans JN, Verhoef C (2011) Anatomical versus nonanatomical resection of colorectal liver metastases: is there a difference in surgical and oncological outcome? World J Surg 35:656–661CrossRefPubMed
11.
go back to reference Ayez N, Burger JW, van der Pool AE, Eggermont AM, Grunhagen DJ, de Wilt JH et al (2013) Long-term results of the “liver first” approach in patients with locally advanced rectal cancer and synchronous liver metastases. Dis Colon Rectum 56:281–287CrossRefPubMed Ayez N, Burger JW, van der Pool AE, Eggermont AM, Grunhagen DJ, de Wilt JH et al (2013) Long-term results of the “liver first” approach in patients with locally advanced rectal cancer and synchronous liver metastases. Dis Colon Rectum 56:281–287CrossRefPubMed
12.
go back to reference de Ridder JAM, van der Stok EP, Mekenkamp LJ, Wiering B, Koopman M, Punt CJA et al (2016) Management of liver metastases in colorectal cancer patients: a retrospective case-control study of systemic therapy versus liver resection. Eur J Cancer 59:13–21CrossRefPubMed de Ridder JAM, van der Stok EP, Mekenkamp LJ, Wiering B, Koopman M, Punt CJA et al (2016) Management of liver metastases in colorectal cancer patients: a retrospective case-control study of systemic therapy versus liver resection. Eur J Cancer 59:13–21CrossRefPubMed
13.
go back to reference van Amerongen MJ, van der Stok EP, Futterer JJ, Jenniskens SF, Moelker A, Grunhagen DJ et al (2016) Short term and long term results of patients with colorectal liver metastases undergoing surgery with or without radiofrequency ablation. Eur J Surg Oncol 42:523–530CrossRefPubMed van Amerongen MJ, van der Stok EP, Futterer JJ, Jenniskens SF, Moelker A, Grunhagen DJ et al (2016) Short term and long term results of patients with colorectal liver metastases undergoing surgery with or without radiofrequency ablation. Eur J Surg Oncol 42:523–530CrossRefPubMed
14.
go back to reference van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S et al (2017) International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer 117:1427–1441CrossRefPubMedPubMedCentral van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S et al (2017) International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer 117:1427–1441CrossRefPubMedPubMedCentral
15.
go back to reference Galjart B, Nierop PMH, van der Stok EP, van den Braak R, Hoppener DJ, Daelemans S et al (2019) Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases. Angiogenesis 22(2):355–368CrossRefPubMedPubMedCentral Galjart B, Nierop PMH, van der Stok EP, van den Braak R, Hoppener DJ, Daelemans S et al (2019) Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases. Angiogenesis 22(2):355–368CrossRefPubMedPubMedCentral
16.
go back to reference Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E et al (2001) Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol 195:336–342CrossRefPubMed Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E et al (2001) Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol 195:336–342CrossRefPubMed
18.
go back to reference Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E et al (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22:1294–1302CrossRefPubMedPubMedCentral Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E et al (2016) Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med 22:1294–1302CrossRefPubMedPubMedCentral
19.
go back to reference Van den Eynden GG, Bird NC, Majeed AW, Van Laere S, Dirix LY, Vermeulen PB (2012) The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin Exp Metastasis 29:541–549CrossRefPubMed Van den Eynden GG, Bird NC, Majeed AW, Van Laere S, Dirix LY, Vermeulen PB (2012) The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin Exp Metastasis 29:541–549CrossRefPubMed
20.
go back to reference Eefsen RL, Vermeulen PB, Christensen IJ, Laerum OD, Mogensen MB, Rolff HC et al (2015) Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin Exp Metastasis 32:369–381CrossRefPubMed Eefsen RL, Vermeulen PB, Christensen IJ, Laerum OD, Mogensen MB, Rolff HC et al (2015) Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin Exp Metastasis 32:369–381CrossRefPubMed
21.
go back to reference Nielsen K, Rolff HC, Eefsen RL, Vainer B (2014) The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol 27:1641–1648CrossRefPubMed Nielsen K, Rolff HC, Eefsen RL, Vainer B (2014) The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol 27:1641–1648CrossRefPubMed
22.
go back to reference Pinheiro RS, Herman P, Lupinacci RM, Lai Q, Mello ES, Coelho FF et al (2014) Tumor growth pattern as predictor of colorectal liver metastasis recurrence. Am J Surg 207:493–498CrossRefPubMed Pinheiro RS, Herman P, Lupinacci RM, Lai Q, Mello ES, Coelho FF et al (2014) Tumor growth pattern as predictor of colorectal liver metastasis recurrence. Am J Surg 207:493–498CrossRefPubMed
23.
go back to reference Punt CJ, Koopman M, Vermeulen L (2017) From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol 14:235–246CrossRefPubMed Punt CJ, Koopman M, Vermeulen L (2017) From tumour heterogeneity to advances in precision treatment of colorectal cancer. Nat Rev Clin Oncol 14:235–246CrossRefPubMed
24.
go back to reference Rahbari NN, Reissfelder C, Schulze-Bergkamen H, Jager D, Buchler MW, Weitz J et al (2014) Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy. BMC Cancer 14:174CrossRefPubMedPubMedCentral Rahbari NN, Reissfelder C, Schulze-Bergkamen H, Jager D, Buchler MW, Weitz J et al (2014) Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy. BMC Cancer 14:174CrossRefPubMedPubMedCentral
25.
go back to reference Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG (2018) Reporting recommendations for tumor marker prognostic studies (REMARK): an abridged explanation and elaboration. J Natl Cancer Inst 110:803–811CrossRefPubMedPubMedCentral Sauerbrei W, Taube SE, McShane LM, Cavenagh MM, Altman DG (2018) Reporting recommendations for tumor marker prognostic studies (REMARK): an abridged explanation and elaboration. J Natl Cancer Inst 110:803–811CrossRefPubMedPubMedCentral
26.
go back to reference DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845CrossRefPubMed DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44:837–845CrossRefPubMed
27.
go back to reference Chetty R, Gill P, Govender D, Bateman A, Chang HJ, Deshpande V et al (2012) International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol 43:1917–1923CrossRefPubMed Chetty R, Gill P, Govender D, Bateman A, Chang HJ, Deshpande V et al (2012) International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems. Hum Pathol 43:1917–1923CrossRefPubMed
28.
go back to reference Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73:2680–2686CrossRefPubMed Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF et al (1994) Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 73:2680–2686CrossRefPubMed
29.
go back to reference Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23CrossRefPubMed Dworak O, Keilholz L, Hoffmann A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23CrossRefPubMed
30.
go back to reference Ryan R, Gibbons D, Hyland JM, Treanor D, White A, Mulcahy HE et al (2005) Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 47:141–146CrossRefPubMed Ryan R, Gibbons D, Hyland JM, Treanor D, White A, Mulcahy HE et al (2005) Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 47:141–146CrossRefPubMed
31.
go back to reference Ehteshami Bejnordi B, Veta M, van Diest PJ, van Ginneken B, Karssemeijer N, Litjens G et al (2017) Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer. JAMA 318:2199–2210CrossRefPubMedPubMedCentral Ehteshami Bejnordi B, Veta M, van Diest PJ, van Ginneken B, Karssemeijer N, Litjens G et al (2017) Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer. JAMA 318:2199–2210CrossRefPubMedPubMedCentral
32.
go back to reference Richman SD, Chambers P, Seymour MT, Daly C, Grant S, Hemmings G et al (2011) Intra-tumoral heterogeneity of KRAS and BRAF mutation status in patients with advanced colorectal cancer (aCRC) and cost-effectiveness of multiple sample testing. Anal Cell Pathol (Amst). 34:61–66CrossRefPubMedPubMedCentral Richman SD, Chambers P, Seymour MT, Daly C, Grant S, Hemmings G et al (2011) Intra-tumoral heterogeneity of KRAS and BRAF mutation status in patients with advanced colorectal cancer (aCRC) and cost-effectiveness of multiple sample testing. Anal Cell Pathol (Amst). 34:61–66CrossRefPubMedPubMedCentral
33.
go back to reference Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O’Dwyer ST, Aziz O (2019) Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine 40:363–374CrossRefPubMedPubMedCentral Bhullar DS, Barriuso J, Mullamitha S, Saunders MP, O’Dwyer ST, Aziz O (2019) Biomarker concordance between primary colorectal cancer and its metastases. EBioMedicine 40:363–374CrossRefPubMedPubMedCentral
Metadata
Title
Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy
Authors
D. J. Höppener
P. M. H. Nierop
E. Herpel
N. N. Rahbari
M. Doukas
P. B. Vermeulen
D. J. Grünhagen
C. Verhoef
Publication date
01-08-2019
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 4/2019
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-019-09975-0

Other articles of this Issue 4/2019

Clinical & Experimental Metastasis 4/2019 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine