Journal of Pathology

J Pathol August 2023; 260: 495–497 EDITORIAL INTRODUCTION

Published online 14 August 2023 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/path.6192

Recent Advances in Pathology: the 2023 Annual Review Issue

of The Journal of Pathology
J Louise Jones1 , Richard Poulsom2 and Philip J Coates3*
1
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK
2
The Pathological Society of Great Britain and Ireland, London, UK
3
Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic

*Correspondence to: PJ Coates, Research Center for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno,
Czech Republic. E-mail: philip.coates@mou.cz

Abstract
The 2023 Annual Review Issue of The Journal of Pathology, Recent Advances in Pathology, contains 12 invited reviews
on topics of current interest in pathology. This year, our subjects include immuno-oncology and computational
pathology approaches for diagnostic and research applications in human disease. Reviews on the tissue microenviron-
ment include the effects of apoptotic cell-derived exosomes, how understanding the tumour microenvironment predicts
prognosis, and the growing appreciation of the diverse functions of fibroblast subtypes in health and disease. We also
include up-to-date reviews of modern aspects of the molecular basis of malignancies, and our final review covers new
knowledge of vascular and lymphatic regeneration in cardiac disease. All of the reviews contained in this issue are
written by expert groups of authors selected to discuss the recent progress in their particular fields and all articles are
freely available online (https://pathsocjournals.onlinelibrary.wiley.com/journal/10969896).
© 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: advanced analytics; apoptosis; artificial intelligence; biomarkers; breast cancer; cancer; cancer-associated fibroblasts; cardiac
regeneration; cell cycle arrest; cell plasticity; cellular senescence; clinical trials; computational pathology; copy number alterations; deep
learning; digital pathology; DNA damage repair; endothelial cells; evolution; exosomes; extracellular vesicles; fibroblast heterogeneity;
fibrosis; genomic complexity; guidelines; heart failure; histopathology; image analysis; immune checkpoint inhibitors; immunotherapy;
immunotherapy failure; keloid scar; lineage tracing; lymphangiogenesis; machine learning; microvesicles; mutations; myocardial infarction;
neovascularisation; oncogenic drivers; pancreatic cancer; patient-derived models; pitfalls; prognostic biomarker; quiescence;
sarcomagenesis; sarcomas; secondary genetic alterations; senescence escape; senolytics; single cell sequencing; skin; spatial profiling;
structural variants; triple-negative breast cancer; tumour heterogeneity; tumour-infiltrating lymphocytes; tumour microenvironment; VEGF;
whole slide images; wound healing

Received 19 July 2023; Accepted 21 July 2023

Conflict of interest statement: JLJ is Editor-in-Chief of The Journal of Pathology. RP is an employee of The Pathological Society of Great Britain and
Ireland and is the Senior Scientific Editor of The Journal of Pathology. PJC is a Senior Editor of The Journal of Pathology.

Immuno-oncology to be solved before reliable computational reporting can

Immuno-oncology, the study of immune cells in
malignancy, has rapidly become an established feature
of importance in pathology, with stand-alone prognostic
information and with the obvious implications as predic-
tive biomarkers and novel therapeutics that target
immune–cancer cell interactions. In the first review article
of this issue, Thagaard, Broeckx, et al discuss the pitfalls
involved in the recent development and application of
computational measurements of tumour-infiltrating
lymphocytes (TILs) in breast cancer [1]. The review comes
from members of The International Immuno-Oncology
Biomarker Working Group, involving 150 departments
worldwide. The authors identify the root causes of
machine learning discordance compared with manual
TIL quantification and discuss validation issues that need
© 2023 The Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org
be incorporated into routine clinical management of
patients and for use in clinical trials. Although the study
concentrates on breast, the same principles apply for TIL
assessment of any tissue. Our second review also comes
from The International Immuno-Oncology Biomarker
Working Group, this time dealing with the impact of
the spatial organisation of TILs [2]. The authors review
the current situation and emphasise the need for
standardisation of data analysis and reporting for future
research of this area. In particular, two approaches for
reporting and analysing spatial data are discussed – raster
versus vector-based – and there is a valuable list of the
various measurements that can be used to define spatial
arrangements. The authors also discuss new investigative
opportunities to improve the clinical utility of two of the
more established immune biomarkers – the breast cancer
stromal TIL score and the colon cancer Immunoscore – as

496
exemplars for these approaches with consideration
of their further development using advanced
spatial analytics. Our third article, from Anguraj
Sadanandam and colleagues at the Department of
Bioengineering at Imperial College and the Institute of
Cancer Research in London, UK, deals with the recent
attempts to treat pancreatic ductal adenocarcinomas with
immunotherapy. The review provides a comprehensive
analysis of the immunotherapies tested in pancreatic
ductal adenocarcinoma (PDAC) to date, their limitations,
and the potential reasons for their failure [3]. The
authors also introduce the potential for bioengineering
techniques such as conjugation of immunotherapies
to antibodies, polymers, or masks to overcome the
immunosuppressive properties of the tumour microenvi-
ronment. Importantly, the review also discusses the
classification of PDACs into cancer, cancer-associated
fibroblast, or immune subtypes for patient selection for
immunotherapy.
Computational pathology
Computational pathology, the application of deep
learning and AI techniques and algorithms to analyse
and interpret histopathology images, continues to grow
rapidly. Our first review article on this field comes from
Gregory Verghese and Anita Grigoriadis and col-
leagues from London, Boston, Melbourne, Chicago,
Mumbai, Antwerp, and Durban, who review the rea-
sons behind the limited adoption of computational
pathology at the present time, despite its obvious
potential value [4]. The authors focus on the patholo-
gists’ perspective and map the current translational
research landscape, evaluate its clinical utility, and
address common challenges that slow clinical imple-
mentation. They conclude by suggesting developments
to improve these techniques for acceptance in the clin-
ical and research settings. The second review in this
section is contributed by Nasir Rajpoot and colleagues
from the University of Warwick, Histofy Ltd, and The
Alan Turing Institute in the UK [5]. This review pro-
vides a detailed summary of the latest developments in
AI techniques applied for computational pathology,
and gives informative insights for identifying specific
challenges and problems that require resolution to
allow clinical implementation of models, including
the need for large, well-curated datasets and uniform
standards and regulatory policies. It concludes with
suggested recommendations for future research in
the field.
Microenvironmental regulation of disease
The role of tissue and tumour microenvironments as
contributing to disease states, particularly malignan-
cies, was largely ignored for many years, where genetic
alterations of the malignant cells were considered to be
© 2023 The Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org
10969896, 2023, 5, Downloaded from https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6192 by Cochrane Qatar, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
JL Jones et al
the most (or the only) important aspect. However, it is
now appreciated that many microenvironmental factors
are important regulators of normal tissues and are often
altered during a variety of pathological states. This
Annual Review Issue contains three reviews of distinct
aspects of this broad field in which there has been
considerable recent progress. The first of these, from
Fu, Sahai, and Wilkins at the Francis Crick Institute and
the Institute of Cancer Research in London, UK, pro-
vides an extensive and up-to-date review of applying
tumour microenvironment analysis for research and
clinical use [6]. The application of advanced analytical
methods and highly multiplexed immunostaining
approaches currently allows high-resolution pictures
of complex tumour microenvironments. AI-based
developments are now able to recognise and quantify
such data in association with clinicopathological infor-
mation and can achieve clinically relevant predictions
as well as discovering novel TME features. These
advances will need to be accompanied by advances
and application of explainability and interpretability
features. Moreover, the ever-expanding datasets,
increased computational power, and the potential for
integration of experimental data mean there is exciting
potential for the future. The next article, from Gregory
and Rimmer in Edinburgh, Scotland, reviews the recent
progress in understanding the properties and effects of
extracellular vesicles (EVs), involved in intercellular
communication and the horizontal transfer of cellular
components [7]. EVs are produced by most cells, if not
all, with healthy cells producing microvesicles and
exosomes, whilst EVs are also produced from cells
undergoing regulated death by apoptosis (termed
ApoEVs). The authors provide an extensive overview
of EVs and their cargoes and emphasise the importance
of ApoEVs (which include ‘apoptotic bodies’ visible in
tissue sections) in the recycling of cellular cargoes, in
regulating inflammatory responses, and in influencing
immunological and cell fate decisions in normal
physiology and diseased states including cancer and
atherosclerosis. In addition, the authors provide an
intriguing perspective on potential clinical applications
of ApoEVs in diagnostics and their potential as
novel therapeutic agents. The final review in this
section relates to the increasing evidence for distinct
subtypes of fibroblasts with diverse functional proper-
ties. In their article, Bensa, Tekkela, and Rognoni from
the Blizard Institute in London, UK, concentrate on
fibroblast subtypes in the skin [8]. They review the
transcriptional heterogeneity of fibroblasts in skin and
other tissues discovered by single cell RNA sequenc-
ing, and the diverse roles of fibroblast subtypes, includ-
ing their well-known roles in extracellular matrix
remodelling and their less-appreciated functions in
immune responses, wound healing, and hair follicle
development. However, understanding the functional
relevance of the newly identified fibroblast clusters is
the key challenge that emerges. The review discusses
these issues of fibroblast heterogeneity evolution in
fibrotic diseases, keloid scars, and cancer.
J Pathol 2023; 260: 495–497
www.thejournalofpathology.com

Recent Advances in Pathology: the 2023 Annual Review Issue
Recent advances in cancer mechanisms and their
implications
We are all aware of the advances in the field of cancer
genetics that have been brought about through increas-
ingly sophisticated nucleic acid sequencing technolo-
gies and bioinformatic approaches to identify important
alterations that occur during tumour formation and
progression. This important area of research in pathol-
ogy continues, incorporating and building on the pre-
vious findings to further refine our understanding of the
biological processes involved and to improve diagno-
sis, prognosis, prediction of response to particular ther-
apies, and identification of alternative therapeutic
targets. Our first review in this broad area of research
comes from Thakur, Haider, and Natrajan at the
Institute of Cancer Research, London, UK [9]. Their
article highlights the implications of tumour heteroge-
neity that is increasingly recognised through single cell
sequencing and digital spatial profiling (confirming
what pathologists have always known by microscopy,
but adding important defining features). The review
focuses on the interplay between tumour cells and their
environment, using breast cancer as an exemplar
tumour type, and discusses the use of lineage tracing
in preclinical models to identify new therapeutic vul-
nerabilities and biomarkers of tumour progression. The
next review, from Dermawan and Rubin in Cleveland,
Ohio, USA, provides a detailed summary of the current
knowledge of the genetic aberrations involved in the
formation and progression of bone and soft tissue
tumours [10]. These tumours are generally grouped as
complex karyotype sarcomas versus tumours with
recurrent genetic alterations, often gene fusions.
Within this latter group, thought to be genomically
‘quiet’, recurrent co-occurring mutations are common
and their nature, function, and importance are a main
theme of this article. In addition, recurrent mutations
are also seen in complex karyotype tumours and
influence tumour biology. The authors discuss in
detail the individual secondary alterations described
in mesenchymal tumours and how they promote
sarcomagenesis mechanistically, organised by the hall-
marks of cancer processes. The third review article on
cancer mechanisms comes from Gorgoulis and col-
leagues in Athens, Greece, and in Manchester,
Dundee, and Surrey, UK [11]. The authors discuss the
recent advances in understanding how cellular senes-
cence acts as a barrier to carcinogenesis, how senes-
cence is induced by a variety of carcinogenic pathways,
and the mechanisms by which cells can escape from
senescence, a process that is distinct from senescence
bypass. The review also discusses how conventional
cancer treatments, which do not target senescent cells,
may benefit from the introduction of senolytic agents
that specifically target these cells, and how assessing
senescence using newly introduced simple staining
methods may be used for personalised therapeutic
approaches.
© 2023 The Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd. www.pathsoc.org
10969896, 2023, 5, Downloaded from https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6192 by Cochrane Qatar, Wiley Online Library on [18/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
497
Cardiac regeneration: mechanisms and therapeutic
opportunities
Our final article in the Annual Review Issue comes from
Berkeley, Tang, and Brittan at the University of Edinburgh,
Scotland and reviews the advances in understanding car-
diovascular regeneration after injury [12]. In particular, the
authors review recent evidence for the ability of the injured
neonatal heart to regenerate and discuss whether inducing
regeneration programmes could be used as a repair mech-
anism for the adult heart after cardiac injury (myocardial
infarct and others). The authors emphasise the vital roles of
neovascularisation and lymphangiogenesis at injured sites
and review the therapeutic strategies employed to date and
their clinical outcomes.
Author contributions statement
All authors were involved in writing and editing the
manuscript. All authors approved the final manuscript
for publication.
References
1. Thagaard J, Broeckx G, Page DB, et al. Pitfalls in machine learning‐
based assessment of tumor‐infiltrating lymphocytes in breast cancer: a
report of The International Immuno‐Oncology Biomarker Working
Group. J Pathol 2023; 260: 498–513.
2. Page D, Broeckz G, Jahangir C, et al. Spatial analyses of immune cell
infiltration in cancer: current methods and future directions: a report of
The International Immuno‐Oncology Biomarker Working Group.
J Pathol 2023; 260: 514–532.
3. Herpels M, Ishihara J, Sadanandam A. The clinical terrain of immuno-
therapies in heterogeneous pancreatic cancer: unravelling challenges and
opportunities. J Pathol 2023; 260: 533–550.
4. Verghese G, Lennerz JK, Ruta D, et al. Computational histopathology
in cancer diagnosis, prognosis and prediction – present day and future
prospects. J Pathol 2023; 260: 551–563.
5. Asif A, Rajpoot K, Graham S, et al. Unleashing the potential of AI for
pathology: challenges and recommendations. J Pathol 2023; 260:
564–577.
6. Fu X, Sahai E, Wilkins A. Application of digital pathology‐based
advanced analytics of tumour microenvironment organisation to pre-
dict prognosis and therapeutic response. J Pathol 2023; 260:
578–591.
7. Gregory CD, Rimmer MP. Extracellular vesicles arising from apo-
ptosis: forms, functions and application. J Pathol 2023; 260:
592–608.
8. Bensa T, Tekkela S, Rognoni E. Skin fibroblast functional heteroge-
neity in health and disease. J Pathol 2023; 260: 609–620.
9. Thakur S, Haider S, Natrajan R. Implications of tumour heterogeneity
on cancer evolution and therapy resistance: lessons from breast
cancer. J Pathol 2023; 260: 621–636.
10. Dermawan JK, Rubin BP. The spectrum and significance of secondary
(co‐occurring) genetic alterations in sarcomas: the hallmarks of
sarcomagenesis. J Pathol 2023; 260: 637–648.
11. Evangelou K, Belogiannis K, Papaspyropoulos A, et al. Escape from
senescence: molecular basis and therapeutic ramifications. J Pathol
2023; 260: 649–665.
12. Berkeley B, Tang MNH, Brittan M. Mechanisms regulating vascular
and lymphatic regeneration in the heart after myocardial infarction.
J Pathol 2023; 260: 666–678.
J Pathol 2023; 260: 495–497
www.thejournalofpathology.com