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 Recent Advances in
Histopathology 23

Massimo Pignatelli MD PhD FRCPath

Dean of Medicine, Nazarbayev University, Astana
Kazakhstan
Adjunct Professor of Pathology, University of Pittsburgh School of Medicine
Pittsburgh, USA

Patrick Gallagher MD PhD FRCPath

Senior Clinical Lecturer, University of Bristol
Bristol, UK

London • Philadelphia • Panama City • New Delhi

© 2014 JP Medical Ltd.
Published by JP Medical Ltd,
83 Victoria Street, London, SW1H 0HW, UK
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Email: [email protected] Web: www.jpmedpub.com

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asserted by them in accordance with the Copyright, Designs and Patents Act 1988.

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to be administered, to verify the recommended dose, formula, method and duration of administration,
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 Preface
We are delighted to present Recent Advances in Histopathology 23 after careful selection of the most
important developments within the field.
The practice of pathology is a constantly evolving speciality. To reflect this, one of the main goals
of this edition is to review the rapid development and application of molecular techniques to
complement the morphological assessment of tissue diagnosis, prognosis and response to treatment.
We have commissioned a wide range of chapters, in order to provide a comprehensive update
of key topics in histopathology for those preparing for their pathology postgraduate exams. We
believe that both generalist as well as specialist consultant and academic histopathologists will find
information of relevance to their daily practice and continued professional development.
This volume of Recent Advances in Histopathology continues the series’ role as a key resource for
pathologists, both in the UK and internationally, who wish to remain up to date with current trends
in modern histopathology. We are especially grateful to the contributors, who responded to our
invitation with enthusiasm and produced well written and interesting chapters in a timely fashion. The
next edition is already under development, and we welcome chapter suggestions from our readers.

Massimo Pignatelli
Patrick Gallagher
March 2014

iii
 Contents

Chapter 1 Antibody-mediated rejection of solid organ allografts 1

Chapter 2 The maternal death autopsy 17
Chapter 3 Classification and treatment of non-small-cell
lung carcinoma 31
Chapter 4 Pathology of obesity 47
Chapter 5 Stratified medicine for cancer: the role of the
histopathologist 61
Chapter 6 Mucosal pathology of the gastric cardia and
Barrett’s oesophagus 73
Chapter 7 Pathology of regenerative and neoplastic
hepatocellular nodules 87
Chapter 8 Serrated lesions of colon and rectum 103
Chapter 9 An update on the pathology of chronic
inflammatory bowel disease 117
Chapter 10 Diagnosis and therapy of gastrointestinal MALT
lymphoma 135
Chapter 11 Medical revalidation for histopathologists 149
Chapter 12 Molecular testing for human papilloma virus 159
Chapter 13 Tensins in health and disease 169
Index 181
 Chapter 1

Antibody-mediated rejection of
solid organ allografts
Margaret M Burke, Desley AH Neil, Annalisa Angelini

IntroductIon
Transplantation is the treatment of choice for end-stage organ failure. Overall survival rates
in the UK [1] (Table1.1) are comparable to those from the international registries. However,
despite improved management of acute cellular rejection (ACR) and of the complications
of immunosuppression, antibody-mediated rejection (AMR) remains a significant cause of
morbidity and mortality early and late after transplantation.
AMR may be asymptomatic or cause allograft dysfunction resistant to therapy for
ACR [2] It affects recipients sensitised with pre-transplant donor-specific antibodies
(DSAs) to human leucocyte antigens (HLAs) or post-transplant de novo HLA or non-HLA
antibodies. Its overall incidence is difficult to estimate as criteria for diagnosis are neither
agreed nor standardised. It may coexist with ACR, the combination being associated with
a worse outcome. Risk factors include younger age, female gender, prior sensitization
to OKT3, cytomegalovirus seropositivity, pregnancy, previous transfusions, surgery and
transplantation, pre-transplant cardiac support with ventricular assist device and pre- and
post-transplant haemodialysis. Treatment options are limited and are associated with
considerable morbidity. Varying combinations of plasmapheresis, immunoadsorption,
intravenous immunoglobulin (Ig) and intensive immunosuppression with drugs such as
mycophenolate mofetil and high-dose cyclophosphamide have limited success. Newer
‘biological’ agents such as monoclonal antibodies to CD20 (rituximab), plasma cells
(bortezomib) and complement C5 (eculizumab) are currently under investigation.
Recently significant progress has been made in our understanding of the pathology and
immunology of AMR. In this chapter, we will briefly summarise the role of antibodies in
pathogenesis of AMR and review the current status of pathological diagnosis of AMR in
kidney, heart, liver and lung allografts.

Margaret M Burke, MB, FRCPath, Department of Pathology, Harefield Hospital, Royal Brompton & Harefield NHS
Foundation Trust, London, UK
Email: [email protected] (for correspondence)
Desley AH Neil, BMedSc, MBBS, PhD, FRCPath, Department of Cellular Pathology, Queen Elizabeth Hospital
Birmingham, Birmingham, UK
Annalisa Angelini, MD, Heart Transplant Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences,
University of Padua, Padua, Italy
2 Antibody-mediated rejection of solid organ allografts

Table 1.1 Mean patient survival 1, 5 and 10 years after solid organ transplantation
(UK data 1998–2010*)
Organ Alive at 1 year (%) Alive at 5 years (%) Alive at 10 years (%)

Kidney
Adult (DBD†) 95.75 88.3 75
Adult (living donor) 98.50 95.5 90
Paediatric (DBD†) 99.25 98.3 94
Paediatric (living donor) 98.50 96.6 93
Heart
Adult 81.25 71 55
Paediatric 92.50 81.6 59
Liver
Adult (DBD†) 88.25 74.6 59
Paediatric (DBD†) 92.75 86.3 81
Lung
Adult 78 53 31
Paediatric NA NA NA

*Figures averaged from NHS Blood and Transplant [1].

†DBD, deceased brain donor.

AntIbodIes And pAthogenesIs of AMr

Capillary endothelial cells (ECs) form the boundary between allograft parenchyma and the
recipient’s blood and are the main target in AMR, mediated by DSAs. Over the last decade,
immunophenotypic and molecular studies of ECs has contributed significantly to our
understanding of their complex interaction with DSAs and its consequences, manifested
in allograft biopsies as microvascular inflammation [3]. All nucleated cells in the body
express Class I HLAs (HLAs A, B and C) on their surface, whilst Class II HLAs (HLAs DP,
DQ and DR) are constitutively expressed on the surface of antigen-presenting cells and ECs
of capillaries, but not larger vessels [4]. Inflammation upregulates Class II HLA expression
by ECs which express receptors on their surface to complement, Fc fragment of Ig and
cytokines such as interferon-gamma. Antibody binding to antigen activates complement
via the classical pathway, generating C4b and C3b which rapidly undergo proteolytic
cleavage to form the stable split degradation products C4d and C3d. These are bound to
ECs and act as indirect tissue markers of complement activation. Immunopathological
detection of capillary C4d deposition in allografts has evolved as a sensitive and specific
diagnostic tool for AMR [5].
Preformed and de novo DSAs are central to pathogenesis of hyperacute and acute
rejection and contribute to late allograft loss [4]. Potential recipients are screened for
panel-reactive antibodies (PRAs) to detect those at risk, and in positive cases complement-
dependent lymphocytotoxicity (CDL) cross-matches – a surrogate marker of DSA – are
performed against potential donors. Different IgG subclasses of preformed DSAs may
vary in pathogenicity. Recipients with IgG3 DSAs are most at risk of graft loss. IgG1 DSAs
 Pathology 3

are the most prevalent, with least risk to the graft [6]. De novo DSAs develop in 20–30% of
transplant recipients, usually to Class II or combined Class I and II HLA antigens [4].
De novo non-HLA antibodies may develop, such as anti-vimentin against endothelium,
and mediate graft damage. Anti-MICA (MHC Class I related chain A) may be associated
with AMR and late allograft failure. Other non-HLA antibodies may be markers of previous
graft injury with exposure of ‘self’ antigens [2]. Transplants have been done successfully
across the ABO blood barrier raising questions about differences in the immune response
to blood group (carbohydrate) antigens versus HLA (glycoprotein) antigens and endothelial
susceptibility to both. Antibodies to glutathione S-transferase T1 (GSTT1) develop in liver
transplant recipients with an allograft genetically mismatched for this protein [7].
CDL is a specific but not sensitive test for detection of anti-HLA antibodies. A recent
important advance in technology is the solid phase assay (Luminex assay) which uses flow
cytometry to detect antibodies to HLAs by the use of single antigens bound to polystyrene
beads. With its greater sensitivity compared with CDL assays, it has led to an increase in the
number of detectable anti-HLA antibodies. Many of these are DSAs, but not all are harmful
to the graft [6]. Recently the addition of labelled C4d or C1q to the Luminex assay has
enabled detection of C4d-fixing or C1q-fixing DSAs which appear to be strongly associated
with poor allograft survival compared with noncomplement-fixing DSAs [6,8]. In a further
refinement of the test single antigen kits to individual HLAs can enable identification of
individual DSAs which can then be quantified by their mean fluorescence intensity (MFI)
level. Increasingly the MFI is used to monitor the impact of DSA-depleting therapies. Whilst
there is considerable interest in these ‘functional assays’, there is no agreement as yet on
their potential value in individual recipients or, in the case of MFIs, what level should be set
as the threshold for significance.
Nonetheless these advances raise the possibility of developing systems of risk stratification
providing there is international standardization of methodology and interpretation of results.
Thus, development of personalised immunosuppression and desensitization in high-risk
DSA-positive potential recipients may become feasible in the future [9].

pAthology
The pathologist is a key member of the clinical team managing allograft recipients. Regular
updates and access to results of biopsy reproducibility studies using digital technology
[10,11] are available in international forums and publications such as those led by the
Banff Foundation for Allograft Pathology (http://www.banfffoundation.org/) and the
International Society for Heart and Lung Transplantation (ISHLT) Annual Scientific
Meetings (http://www.ishlt.org/). This ensures continual refinements of grading systems
for biopsy diagnosis of AMR in the different organs in the light of outcome data from
international multicentre studies.
In 2004, a National Institute of Health conference on diagnosis of AMR in solid
organ allografts proposed a generic classification system based on a multidisciplinary
approach using serology for DSAs, C4d deposition in tissues, histopathological changes
and graft dysfunction [12] (Table 1.2). Recent molecular studies, mainly in kidney, have
highlighted the importance of the histopathological features of AMR in the absence
of C4d positivity, and the combination of C4d and histology without a proven DSA in
diagnosing AMR [3].
4 Antibody-mediated rejection of solid organ allografts

Table 1.2 Modified NIH proposal for working classification of antibody-mediated rejection*
Antibody-mediated rejection:
Allograft dysfunction, histopathological findings, capillary C4d deposition, circulating DSAs (HLA or non-HLA)
Asymptomatic antibody-mediated rejection:
Histopathological findings, capillary C4d deposition, circulating DSAs (HLA or non-HLA)
Silent/latent antibody-mediated response†:
Capillary C4d deposition and/or circulating DSAs (HLA or non-HLA)

*Adapted from Takemoto et al. [12].

†Molecular studies in kidney suggest that C4d or DSAs alone with positive histopathology may equate with antibody-
mediated rejection [3,17]
DSAs, donor-specific antibodies; HLA, human leucocyte antigens.

In kidney and heart allografts acute AMR is manifested as microvascular inflammation

with capillary endothelial activation, accumulation of intravascular (IV) inflammatory cells
and capillary C4d deposition as a sign of complement activation [13–15]. The picture is less
clear in liver and lung allografts [16,17]. Other pathology such as oedema, haemorrhage,
microvascular thrombosis and tissue necrosis may reflect increasing severity of AMR.
Capillary C4d deposition appears as intensely staining granular endothelial deposits. It
is scored by intensity and distribution of deposition in kidney and heart allografts. A scoring
system has not been agreed universally for lung and liver allografts. Changes of long-
standing AMR (chronic AMR) are described in biopsies from renal, but not other allografts,
although AMR contributes, with ACR and nonimmune factors, to the development of
chronic rejection in cardiac and pulmonary allografts, manifested as cardiac allograft
vasculopathy (CAV) and obliterative bronchiolitis (OB), respectively.
The ‘gold standard’ tissue staining technique for C4d is immunofluorescence (IF) using
a monoclonal antibody. Polyclonal antibodies are available for use on paraffin wax sections
with immunohistochemistry (IHC) which is the method of choice with, or instead of, IF for
many pathologists. However, a small number of studies have compared IHC with IF and, as
exemplified in the heart, show variable sensitivity for IHC [18]. Hence, a low threshold for
reporting positivity is needed when using IHC.
Properly standardised technology is important to avoid pitfalls in interpretation of
C4d, especially using IHC. Controls for C4d should include tissue with known hyperacute
rejection or AMR. C4d deposition in arterial endothelium and artefacts such as nonspecific
staining of arteriolar elastic lamina are useful as internal positive controls. Interstitial
staining may interfere with evaluation of capillary deposition. Intense serum staining
should not be mistaken for a positive result as it lacks the circumferential granular staining
typical for endothelial C4d deposition. Capillary C4d deposition may also occur in lesions
not relevant to diagnosis of AMR such as biopsy site scars in the heart. Other pathologies
such as hyaline membranes in diffuse alveolar damage, necrotic myocytes and necrotic
hepatocytes may be positive.
The pathological features of AMR specific to each organ will be presented in the
following sections. They are best developed and understood in renal allografts.

Kidney
The presentation of renal AMR may be acute (aAMR) with rapid reduction in renal
function, often associated with proteinuria, or may be more insidious [13]. Ongoing
 Pathology 5

untreated, partially treated or multiple episodes of aAMR can result in structural changes
in the allograft. Once these develop the process is called chronic AMR (cAMR) [9]. The
histological features depend on the timing of the biopsy.
By Banff criteria the diagnosis of renal AMR is multidisciplinary and requires DSA
positivity, C4d deposition in peritubular capillaries (PTCs) and histological features of
AMR [3,19]. If only two of the three features are present, or the pathologist is unaware of the
DSA data then it is classified as suspicious of AMR. However these criteria are increasingly
recognised as missing AMR with clinical impact [13,20].

Histopathology
In aAMR microcirculatory changes occur in PTCs and glomerular capillaries (GCs),
termed peritubular capillaritis and transplant glomerulitis, respectively (Figure 1.1a and
b), with accumulation of macrophages and T lymphocytes [13,21]. In severe cases, there is
thrombotic microangiopathy (TMA) with thrombi in arterioles and/or glomeruli [13]. The
other cause of TMA in this setting is acute calcineurin inhibitor (CNI) toxicity. Fibrinoid
necrosis in larger vessels is recognised as a feature of AMR [3] as is transmural and intimal

a b

c d

Figure 1.1 Acute renal antibody-mediated rejection. (a) Glomerulitis: Periodic acid Schiff-stained section of
glomerulus showing segmental capillary loops plugged with inflammatory cells (arrow). Most other capillary loops
are empty. (b) Peritubular capillaritis: Haematoxylin and eosin-stained section of vacuolated tubular epithelium
indicating acute tubular injury, interstitial oedema separating the tubules and peritubular capillaritis (arrows) with
intravascular inflammatory cells. (c) C4d-immunostained section showing deposition on endothelium of glomerular
capillaries and (d) on peritubular capillaries.
6 Antibody-mediated rejection of solid organ allografts

arteritis [13]. Peritubular capillaritis should be assessed only in cortex as it is less specific in
medulla, where it may be seen in ascending infection.
In cAMR there is reduplication of glomerular basement membrane (GBM) and
peritubular capillary basement membranes (PTCBMs) [13,22]. On light microscopy, this
is seen as double contours of GBMs, termed transplant glomerulopathy. Other causes
of double contours must be excluded such as recurrent or de novo immune complex
glomerulonephritis and chronic TMA due to other causes. Chronic vascular rejection,
consisting of fibromuscular intimal thickening, with minimal elastosis, is seen as a
consequence of cAMR, although other factors such as increased cold ischaemia time and
CMV infection may be involved.

Immunohistochemistry
C4d deposition is seen in PTCs and/or GCs (Figure 1.1 c and d) [23], but only peritubular
capillary deposition is assessed as part of Banff criteria for diagnosis of AMR. By IF, Banff
criteria state that 50% of PTCs need to show positive staining to be considered positive
[3]. However, recent evidence suggests that any staining has an impact on long-term graft
survival [23]. On IF GC C4d deposition may be difficult to assess because of glomerular
autofluorescence. The presence of glomerular C4d positivity increases the risk of long-term
graft loss. The medulla is the most sensitive area in which to detect C4d deposition in PTCs.
C4d deposition in atrophic areas has been shown to affect long-term graft survival [3]. With
the recent understanding of the role of natural killer (NK) cells in AMR, a marker for NK
cells may help in diagnosis [20].

Electron microscopy
The earliest feature of AMR is swelling of ECs, with increase in organelles of GC and PTC.
Within glomeruli this is associated with or followed by electron-lucent widening and
accumulation of debris on the subendothelial side of the GBM [24,25]. With more severe,
AMR there is necrosis of ECs and accumulation of platelets, both features of TMA.
Untreated glomerular changes progress with deposition of a new layer of GBM just
under the EC layer (Figure 1.2a). There may be interposition of mesangial cells in the
GBM, but there are no electron dense deposits, a feature which allows differentiation from
immune complex-mediated reduplication of the GBM. Parallel changes occur in PTCs with
reduplication of the PTC basement membrane (Figure 1.2b) [13,22]. Three to four layers
are evidence of early cAMR and five or more layers are diagnostic of cAMR [3,24]. The
ultrastructural features of cAMR precede the light microscopic features of double contours.

Molecular studies in renal AMR

Molecular studies on C4d-positive biopsies have helped to further the understanding
of the pathology of AMR. Endothelial transcripts, a marker of endothelial activation, are
upregulated and associated with NK cell transcripts, indicating a potential role of NK cells
in AMR. By looking at AMR transcripts across a broad spectrum of biopsies, the importance
of microvascular inflammation as a marker of AMR has been highlighted and is potentially
more sensitive than C4d staining [3].

Heart
The incidence of cardiac AMR is estimated as 10–20%. It may occur early or late
after transplantation. By recently established ISHLT criteria, diagnosis is based on
morphological and immunopathological criteria alone [14,15].
 Pathology 7

Figure 1.2 Chronic renal antibody-

mediated rejection. (a) Electron
micrograph of glomerular capillary
wall showing endothelial cells
(curved arrows) lining the capillary
loop, and epithelial cells (Epi) lining
the outer aspect of the glomerular
basement membrane (GBM).
There is a new layer of glomerular
basement membrane (straight
arrows) on the subendothelial
GBM aspect, separated from the original
Epi glomerular basement membrane
by an area of electron lucency.
(b) Electron micrograph of part
of a peritubular capillary. There
a b
is reduplication of the basement
membrane with eight to nine layers
(}) beneath the endothelium (arrow).

Background
Several studies over the last two decades have correlated microvascular inflammation and
capillary C4d positivity with DSA positivity, graft dysfunction, CAV and a poor outcome
[26,27]. Diagnostic criteria for AMR were included in the 2005 revision of ISHLT’s 1990 working
formulation for biopsy diagnosis of rejection [28]. In 2010, the requirements outlined in 2005
for DSA positivity and graft dysfunction were dropped after acceptance of asymptomatic AMR
as an entity, with the diagnosis of AMR to be made henceforth by pathological criteria alone
[2]. In 2011, a preliminary grading system for AMR was drawn up and published by members
of ISHLT’s Pathology Council [14] with publication of the definitive version in 2013 [15]. It
remains subject to review as experience of its utility increases.

Definitions and grading

The pathological features of AMR, or ‘pathologic AMR’ (pAMR), are graded on the
combination of histopathological and immunopathological findings. pAMR 1 is
characterised by either histopathological changes [pAMR1(h+)] or immunopathological
findings [pAMR1(i+)]. pAMR2 is characterised by both histopathological changes
and immunopathological findings. pAMR3, or severe AMR, is characterised by
histopathological and immunopathological evidence of extensive myocardial damage and
often disruption of the microcirculation. Concomitant ACR is frequently found and should
be graded separately [14,15,26,28].

Histopathology
Diffuse myocardial microvascular inflammation is the hallmark of cardiac AMR (Figure
1.3a) and is associated with capillary C4d deposition and, often, circulating DSAs with/
without cardiac allograft dysfunction [14]. In pAMR1 (h+) and pAMR2 capillaries are
distended, with lumens narrowed by plump activated ECs and ‘plugs’ of IV macrophages
[26,29] (Figure 1.3b and c). In pAMR3 there is oedema, vasculitis, haemorrhage,
microvascular thrombosis, capillary damage and myocyte necrosis with neutrophil
infiltration and karyorrhectic debris, usually in the clinical setting of profound irretrievable
allograft dysfunction. Occasional IV macrophages may be also seen in the quiescent state,
ACR, ischaemic injury, infection and healing biopsy sites.
8 Antibody-mediated rejection of solid organ allografts

a b

c d

Figure 1.3 Cardiac antibody-mediated rejection. (a) Haematoxylin and eosin-stained section of myocardium which
shows diffuse microvascular inflammation. (b) Capillary endothelial cells are prominent (short arrows) and lumens
contain mononuclear cells (long arrows). (c) The intravascular cells are CD68-positive, thus confirming them as
macrophages. (d) There is diffuse capillary C4d deposition.

Immunopathology
Antibodies for biopsy evaluation of AMR are C4d and CD68 using IHC and C3d, C4d and
HLA-DR using IF [14,15]. Some pathologists use either HLA-DR by IF or CD31/CD34 by
IHC to assess capillary integrity which may be lost in pAMR3 or after repeated episodes
of lesser grades of pAMR. In pAMR1 (i+) and pAMR2 a positive C4d result by IHC and IF
is multifocal (>50% of intact myocardium) or diffuse capillary deposition of any intensity
[14,15] (Figure 1.3d). Diffuse weak capillary C4d deposition may reflect previous or
resolving AMR. Focal strong C4d deposition by IHC (>10–50% of intact myocardium) may
represent evolving AMR and the pathologist should recommend close monitoring of graft
function and peripheral blood DSA studies. In pAMR3 C4d deposition may be absent, weak
or multifocal because of endothelial damage. All C4d-positive cases should be followed
up by IHC/IF until negative. Perimyocytic C4d deposition is occasionally observed, but its
significance is currently unknown. Capillaries in Quilty lesions, scars and ischaemic injury
may also stain but are not relevant to diagnosis of AMR at this time. Results of IF staining
with the monoclonal antibody to C3d may predict AMR [30]. Results of IHC staining with
the polyclonal antibody to C3d are neither specific nor sensitive for AMR and are not
recommended at this time.
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