Edwards, Joanne

Horgan, Paul G.

McMillan, Donald C.

Park, James H.

Roxburgh, Campbell S.D.

English

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     Park, J. H., Roxburgh, C. S.D., Edwards, J., Horgan, P. G. and McMillan, D. C. (2017) In reply to "Hynes S.O. et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study". Histopathology, 71(2), pp. 326-327.  There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.  Park, J. H., Roxburgh, C. S.D., Edwards, J., Horgan, P. G. and McMillan, D. C. (2017) In reply to "Hynes S.O. et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study". Histopathology, 71(2), pp. 326-327. (doi:10.1111/his.13195) This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.      http://eprints.gla.ac.uk/137704/            Deposited on: 02 March 2017             UNIVERSITY DEPARTMENT OF SURGERY Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF  Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk        9th February 2017  Dear Editor,  In reply to “Hynes S.O. et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study”  We read with interest the recent study by Hynes et al 1.  In this study of 445 patients undergoing surgical resection of stage II/III colon cancer, the presence of a conspicuous peritumoural inflammatory cell infiltrate, as measured by the Crohn’s like reaction (CLR) and a modification of the Klintrup-Mäkinen grade (examining only the lymphoid cell population), was associated with improved prognosis.  A high proportion of tumour-associated stroma, as measured by a ‘global’ assessment of the tumour stroma percentage (TSP) but not ‘focal’ assessment, was also associated with poorer survival.  The CLR and global assessment of TSP demonstrated acceptable levels of inter- and intraobserver variability, whereas the peritumoural lymphoid infiltrate and focal TSP assessment did not.  Identifying the complimentary prognostic value of both the inflammatory infiltrate and the TSP, the authors proposed a combined ‘fibroinflammatory score’, which stratified survival independent of stage, MSI status and chemotherapy use.  We however wish to raise a number of points for consideration.  Acknowledging that it is the lymphoid population that holds most prognostic value within the inflammatory infiltrate, the proposed modification of the Klintrup-Mäkinen grade has not been validated as a reliable and reproducible measure.  Although encompassing all inflammatory cell types, the original Klintrup-Mäkinen grade has been validated internationally as a reproducible, stage-independent characteristic in colorectal cancer 2, 3.  Therefore, it would be more readily          UNIVERSITY DEPARTMENT OF SURGERY Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF  Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk     applicable in routine clinical practice.  Furthermore, given the high degree of interobserver variability of the modified Klintrup-Mäkinen grade, assessment of specific lymphoid populations may require immunohistochemical staining for immune cell subsets.  The Immunoscore, reflective of CD3+ and CD8+ T-lymphocyte density, is one such example4.   Hynes and colleagues employed semi-quantitative assessment of the CLR as described by Graham and Appelman, however it has recently been reported that more objective assessment of lymphoid follicle density or size increases not only reproducibility, but also prognostic value 5.  Similarly, although not associated with survival, it is of interest that the ‘focal’ assessment of TSP reflects a refinement of the previously described ‘global’ assessment, and again has previously been internationally validated in the context of retrospective analysis of clinical trial data 6, 7.  Finally, although the authors must be congratulated on further supporting the routine use of both the inflammatory infiltrate and stroma to inform prognosis of patients with colorectal cancer, the presently described ‘fibroinflammatory score’ is not the first tumour microenvironment score to consider combined assessment of both elements.  Several groups have recognised the relative importance of both the inflammatory infiltrate and tumour-associated stroma; ranging from the Jass criteria described in 1986 8, to the more recently described consensus molecular subtypes associated with distinctive tumour microenvironment phenotypes 9.   Recently, we have described a tumour microenvironment score based on combined assessment of the Klintrup-Mäkinen grade and TSP 10.  This score, termed the Glasgow Microenvironment Score (GMS), stratified survival independent of stage, mismatch repair status and chemotherapy use.  The GMS also allows further insight into the evolution of the tumour microenvironment; a high TSP was rare and had no prognostic value in the presence of a high Klintrup-Mäkinen grade, only stratifying survival of those with a low density inflammatory infiltrate. These results were similarly observed when examining the combined prognostic value of the Immunoscore and TSP 11.  Taken together, we believe these results suggest that it is loss of the anti-tumour inflammatory infiltrate that promotes development of the tumour-associated stroma.  Given the reliance of the GMS on validated, readily         UNIVERSITY DEPARTMENT OF SURGERY Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF  Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk     reproducible assessments, and its utilisation of routine pathological specimens, we would encourage the authors of the present study to adopt a similar approach to assessment of the tumour microenvironment in patients with colorectal cancer. Yours sincerely,  Mr James Park, Clinical Lecturer in Colorectal Surgery Dr Campbell Roxburgh, Senior Clinical Lecturer Dr Joanne Edwards, Senior Lecturer Professor Paul Horgan, Professor of Surgery Professor Donald McMillan, Professor of Surgical Sciences    References  1. Hynes SO, Coleman HG, Kelly PJ et al. Back to the future: Routine morphological assessment of the tumour microenvironment is prognostic in stage ii/iii colon cancer in a large population-based study. Histopathology 2017. 2. Klintrup K, Makinen JM, Kauppila S et al. Inflammation and prognosis in colorectal cancer. Eur J Cancer 2005;41;2645-2654. 3. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC. Comparison of the prognostic value of inflammation-based pathologic and biochemical criteria in patients undergoing potentially curative resection for colorectal cancer. Ann Surg 2009;249;788-793. 4. Galon J, Mlecnik B, Bindea G et al. Towards the introduction of the 'immunoscore' in the classification of malignant tumours. J Pathol 2014;232;199-209. 5. Kim JH, Kim KJ, Bae JM et al. Comparative validation of assessment criteria for crohn-like lymphoid reaction in colorectal carcinoma. J Clin Pathol 2015;68;22-28. 6. Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS. The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann Oncol 2014;25;644-651.          UNIVERSITY DEPARTMENT OF SURGERY Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF  Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk       7. Huijbers A, Tollenaar RA, v Pelt GW et al. The proportion of tumor-stroma as a strong prognosticator for stage ii and iii colon cancer patients: Validation in the victor trial. Ann Oncol 2013;24;179-185. 8. Jass JR. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 1986;39;585-589. 9. Guinney J, Dienstmann R, Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21;1350-1356. 10. Park JH, McMillan DC, Powell AG et al. Evaluation of a tumor microenvironment-based prognostic score in primary operable colorectal cancer. Clin Cancer Res 2015;21;882-888. 11. Park JH, McMillan DC, Edwards J, Horgan PG, Roxburgh CSD. Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer. Oncoimmunology 2015;5;e1098801.  

In reply to "Hynes S.O. et al. Back to the future: routine morphological assessment of the tumour microenvironment is prognostic in stage II/III colon cancer in a large population-based study"

Enlighten: Publications

 
 
 
 
 
Park, J. H., Roxburgh, C. S.D., Edwards, J., Horgan, P. G. and McMillan, 
D. C. (2017) In reply to "Hynes S.O. et al. Back to the future: routine 
morphological assessment of the tumour microenvironment is prognostic in 
stage II/III colon cancer in a large population-based study". Histopathology, 
71(2), pp. 326-327.  
There may be differences between this version and the published version. 
You are advised to consult the publisher’s version if you wish to cite from 
it. 
 
Park, J. H., Roxburgh, C. S.D., Edwards, J., Horgan, P. G. and McMillan, 
D. C. (2017) In reply to "Hynes S.O. et al. Back to the future: routine 
morphological assessment of the tumour microenvironment is prognostic in 
stage II/III colon cancer in a large population-based study". Histopathology, 
71(2), pp. 326-327. (doi:10.1111/his.13195) This article may be used for 
non-commercial purposes in accordance with Wiley Terms and Conditions 
for Self-Archiving.  
 
 
 
 
http://eprints.gla.ac.uk/137704/ 
     
 
 
 
 
 
 
Deposited on: 02 March 2017 
 
 
 
 
 
  
 
 
 
 
 
UNIVERSITY DEPARTMENT OF SURGERY 
Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF 
 
Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk 
 
 
 
 
 
 
 
9th February 2017 
 
Dear Editor, 
 
In reply to “Hynes S.O. et al. Back to the future: routine morphological assessment of the 
tumour microenvironment is prognostic in stage II/III colon cancer in a large population-
based study” 
 
We read with interest the recent study by Hynes et al 1.  In this study of 445 patients undergoing 
surgical resection of stage II/III colon cancer, the presence of a conspicuous peritumoural 
inflammatory cell infiltrate, as measured by the Crohn’s like reaction (CLR) and a modification 
of the Klintrup-Mäkinen grade (examining only the lymphoid cell population), was associated 
with improved prognosis.  A high proportion of tumour-associated stroma, as measured by a 
‘global’ assessment of the tumour stroma percentage (TSP) but not ‘focal’ assessment, was also 
associated with poorer survival.  The CLR and global assessment of TSP demonstrated 
acceptable levels of inter- and intraobserver variability, whereas the peritumoural lymphoid 
infiltrate and focal TSP assessment did not.  Identifying the complimentary prognostic value of 
both the inflammatory infiltrate and the TSP, the authors proposed a combined 
‘fibroinflammatory score’, which stratified survival independent of stage, MSI status and 
chemotherapy use. 
 
We however wish to raise a number of points for consideration.  Acknowledging that it is the 
lymphoid population that holds most prognostic value within the inflammatory infiltrate, the 
proposed modification of the Klintrup-Mäkinen grade has not been validated as a reliable and 
reproducible measure.  Although encompassing all inflammatory cell types, the original Klintrup-
Mäkinen grade has been validated internationally as a reproducible, stage-independent 
characteristic in colorectal cancer 2, 3.  Therefore, it would be more readily  
 
  
 
 
 
 
 
UNIVERSITY DEPARTMENT OF SURGERY 
Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF 
 
Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk 
 
 
 
 
applicable in routine clinical practice.  Furthermore, given the high degree of interobserver 
variability of the modified Klintrup-Mäkinen grade, assessment of specific lymphoid populations 
may require immunohistochemical staining for immune cell subsets.  The Immunoscore, 
reflective of CD3+ and CD8+ T-lymphocyte density, is one such example4.  
 
Hynes and colleagues employed semi-quantitative assessment of the CLR as described by 
Graham and Appelman, however it has recently been reported that more objective assessment of 
lymphoid follicle density or size increases not only reproducibility, but also prognostic value 5.  
Similarly, although not associated with survival, it is of interest that the ‘focal’ assessment of 
TSP reflects a refinement of the previously described ‘global’ assessment, and again has 
previously been internationally validated in the context of retrospective analysis of clinical trial 
data 6, 7. 
 
Finally, although the authors must be congratulated on further supporting the routine use of both 
the inflammatory infiltrate and stroma to inform prognosis of patients with colorectal cancer, the 
presently described ‘fibroinflammatory score’ is not the first tumour microenvironment score to 
consider combined assessment of both elements.  Several groups have recognised the relative 
importance of both the inflammatory infiltrate and tumour-associated stroma; ranging from the 
Jass criteria described in 1986 8, to the more recently described consensus molecular subtypes 
associated with distinctive tumour microenvironment phenotypes 9.   
Recently, we have described a tumour microenvironment score based on combined assessment of 
the Klintrup-Mäkinen grade and TSP 10.  This score, termed the Glasgow Microenvironment 
Score (GMS), stratified survival independent of stage, mismatch repair status and chemotherapy 
use.  The GMS also allows further insight into the evolution of the tumour microenvironment; a 
high TSP was rare and had no prognostic value in the presence of a high Klintrup-Mäkinen grade, 
only stratifying survival of those with a low density inflammatory infiltrate. These results were 
similarly observed when examining the combined prognostic value of the Immunoscore and TSP 
11.  Taken together, we believe these results suggest that it is loss of the anti-tumour inflammatory 
infiltrate that promotes development of the tumour-associated stroma.  Given the reliance of the 
GMS on validated, readily  
  
 
 
 
 
 
UNIVERSITY DEPARTMENT OF SURGERY 
Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF 
 
Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk 
 
 
 
 
reproducible assessments, and its utilisation of routine pathological specimens, we would 
encourage the authors of the present study to adopt a similar approach to assessment of the 
tumour microenvironment in patients with colorectal cancer. 
Yours sincerely, 
 
Mr James Park, Clinical Lecturer in Colorectal Surgery 
Dr Campbell Roxburgh, Senior Clinical Lecturer 
Dr Joanne Edwards, Senior Lecturer 
Professor Paul Horgan, Professor of Surgery 
Professor Donald McMillan, Professor of Surgical Sciences 
 
  
References 
 
1. Hynes SO, Coleman HG, Kelly PJ et al. Back to the future: Routine morphological 
assessment of the tumour microenvironment is prognostic in stage ii/iii colon cancer in a large 
population-based study. Histopathology 2017. 
2. Klintrup K, Makinen JM, Kauppila S et al. Inflammation and prognosis in colorectal 
cancer. Eur J Cancer 2005;41;2645-2654. 
3. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC. Comparison of the 
prognostic value of inflammation-based pathologic and biochemical criteria in patients 
undergoing potentially curative resection for colorectal cancer. Ann Surg 2009;249;788-793. 
4. Galon J, Mlecnik B, Bindea G et al. Towards the introduction of the 'immunoscore' in the 
classification of malignant tumours. J Pathol 2014;232;199-209. 
5. Kim JH, Kim KJ, Bae JM et al. Comparative validation of assessment criteria for crohn-
like lymphoid reaction in colorectal carcinoma. J Clin Pathol 2015;68;22-28. 
6. Park JH, Richards CH, McMillan DC, Horgan PG, Roxburgh CS. The relationship 
between tumour stroma percentage, the tumour microenvironment and survival in patients with 
primary operable colorectal cancer. Ann Oncol 2014;25;644-651. 
 
 
  
 
 
 
 
 
UNIVERSITY DEPARTMENT OF SURGERY 
Royal Infirmary, Level 2, New Lister Building, Castle Street, Glasgow. G4 0SF 
 
Telephone 0141-201 8676.  Fax 0141-211 4943. Email: james.park@glasgow.ac.uk 
 
 
 
 
 
 
7. Huijbers A, Tollenaar RA, v Pelt GW et al. The proportion of tumor-stroma as a strong 
prognosticator for stage ii and iii colon cancer patients: Validation in the victor trial. Ann Oncol 
2013;24;179-185. 
8. Jass JR. Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 
1986;39;585-589. 
9. Guinney J, Dienstmann R, Wang X et al. The consensus molecular subtypes of colorectal 
cancer. Nat Med 2015;21;1350-1356. 
10. Park JH, McMillan DC, Powell AG et al. Evaluation of a tumor microenvironment-based 
prognostic score in primary operable colorectal cancer. Clin Cancer Res 2015;21;882-888. 
11. Park JH, McMillan DC, Edwards J, Horgan PG, Roxburgh CSD. Comparison of the 
prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated 
stroma in patients with primary operable colorectal cancer. Oncoimmunology 2015;5;e1098801. 
 


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