Not all tumour necrosis is granular necrosis: authors' response

Fuchs et al.1Fuchs T.L. Chou A. Ahadi M. et al.Necrosis is an independent predictor of disease-free and overall survival in pancreatic well-differentiated neuroendocrine tumours (NETs): a proposal to include it in grading systems.Pathology. 2022; 54: 855-862Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar examine a series of 110 pancreatic neuroendocrine tumours for the presence of necrosis. They propose that this parameter be incorporated into the World Health Organization grading system for these tumours, which is currently confined to mitotic rate and Ki-67 index.2WHO Classification of Tumours Editorial BoardWHO Classification of Tumours: Digestive System Tumours.5th ed, Vol. 1. IARC, Lyon2019Google Scholar Analyses of the series showed 12 tumours to have necrosis; however, it is uncertain as to the nature of the necrosis present within their series of cases. In their Materials and Methods they note that ‘the presence of any tumour necrosis was considered positive’. The authors further reinforce this in the caption of their Fig. 1 where it is stated that ‘different tumours demonstrated different types of necrosis, but we emphasise that all these patterns are considered positive for necrosis’. In the text of the report no details are provided as to the different types of tumour necrosis encountered. However, this is alluded to in the caption of their Fig. 1 where examples of necrosis show central comedo-type necrosis, zones of geographic necrosis with ghost outlines of necrotic tumour cells, and focal punctate necrosis with nuclear debris. In a consensus report we have recently discussed the types of necrosis seen in malignancies. This report described the features of a unique form of necrosis seen in tumours, for which we have proposed the term granular necrosis.3Samaratunga H. Delahunt B. Srigley J.R. et al.Granular necrosis: a distinctive form of cell death in malignant tumours.Pathology. 2020; 52: 507-514Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The morphology of this type of necrosis is characteristic, consisting of well defined foci of granular nuclear and cytoplasmic debris with extensive karyorrhexis and loss of underlying architecture. This clearly differentiates this type of necrosis from coagulative necrosis where the underlying architecture is retained and the tumour cells themselves are mummified, without nuclear debris.3Samaratunga H. Delahunt B. Srigley J.R. et al.Granular necrosis: a distinctive form of cell death in malignant tumours.Pathology. 2020; 52: 507-514Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar It is evident that in the study of Fuchs et al. that their series contained tumours exhibiting granular necrosis (which includes necrosis described as comedonecrosis) or coagulative necrosis. Distinguishing between granular necrosis and coagulative necrosis in tumours is not a meaningless academic exercise, as the pathogenesis of these two types of necrosis is quite different. Coagulative necrosis develops as the result of ischaemia, while the pathogenesis of granular necrosis is apparently molecular in origin. Recent studies have emphasised that granular necrosis is an intrinsic feature of aggressive tumours and may involve necroptosis, which is dependent on receptor interacting protein kinase signalling with up-regulation of tumour necrosis factor.4Hanson B. Necroptosis; a new way of dying?.Cancer Biol Ther. 2016; 17: 899-910Crossref PubMed Scopus (63) Google Scholar, 5Al-Lamki R.S. Lu W. Manalo P. et al.Tubular epithelial cells in renal clear cell carcinoma express high RIPK1/3 and show increased susceptibility to TNF receptor 1-induced necroptosis.Cell Death Dis. 2016; 30: e2287Crossref Scopus (29) Google Scholar, 6Galluzzi L. Vitale I. Aaronson S.A. et al.Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death.Cell Death Differ. 2018; 25: 486-541Crossref PubMed Scopus (3296) Google Scholar Inactivation of hypoxia inducible factor may also contribute.7Bredholt G. Mannelqvist M. Stefansson I.M. et al.Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.Oncotarget. 2015; 6: 39676-39691Crossref PubMed Scopus (108) Google Scholar In addition to a difference in pathogenesis for each of the types of necrosis, in the few studies that have made this differentiation, it has been shown that they have differing prognostic significance.8Dagher J. Delahunt B. Rioux-Leclercq N. et al.Assessment of tumour-associated necrosis provides prognostic information additional to World Health Organization/International Society of Urological Pathology grading for clear cell renal cell carcinoma.Histopathology. 2019; 74: 284-290Crossref PubMed Scopus (18) Google Scholar,9Collins J. Epstein J.I. Prognostic significance of extensive necrosis in renal cell carcinoma.Hum Pathol. 2017; 66: 108-114Crossref PubMed Scopus (15) Google Scholar The survival analysis reported by Fuchs et al. is further confounded by the inclusion of tumours that had been investigated by fine needle aspiration before definitive surgery (two cases) or intra-operatively (one case). This has the potential to result in trauma-related necrosis that would have no independent prognostic significance. These cases should have been deleted from the survival statistical analyses. Interestingly, the study of Fuchs et al. also investigated the presence of vascular invasion as a prognostic factor and noted that tumour was present in vessels in 33 cases in their series. They showed on univariable analyses, that the presence of this feature was significantly associated with both overall survival and disease free survival, and for disease free survival, this significance was retained on multivariable analysis. This raises the question, is the presence of coagulative necrosis a surrogate marker of vascular invasion and does this have independent prognostic significance? The inclusion of multiple types of necrosis in the survival studies prevents elucidation of vascular invasion as a potentially important additional prognostic factor. If this is confirmed, it could also be included as a grading parameter for pancreatic low grade/well differentiated neuroendocrine tumours. The authors state that there are no conflicts of interest to disclose.