A Practical Approach to Vascular Pathology in Pulmonary Hypertension

8/12/2019 A Practical Approach to Vascular Pathology in Pulmonary Hypertension

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A practical approach tovascular pathology inpulmonary hypertensionKatrien Grunberg

Wolter J Mooi

AbstractPulmonary hypertension (PH) is the common physiological denominator

in an otherwise heterogeneous disease. While pulmonary hypertension

itself is not a pathologists diagnosis, various patterns of pulmonary vas-

culopathy may be recognized in pulmonary hypertension. These patterns

of vasculopathy are at the basis of classification, as they point towards

(groups of) risk factors and aetiology. However, as surgical lung biopsy

is a high risk procedure in PH, the role for histopathological evaluation

is now mainly in retrospective evaluation on explanted lung or tissue ob-

tained at autopsy, taking clinical work-up, including haemodynamic

parameters and HRCT imaging, into account. Such multidisciplinary eval-

uation and classification may help assess the prognosis, including risk of

recurrence in a transplant, and possible risk of PH in family members.

More generally, systematic evaluation may identify clues as to pathogen-

esis and may help to fill the knowledge gap between histopathology and

non-invasive diagnostic procedures such as imaging. This will hopefully

eventually lead to a patho-physiologic rationale for classification, and

to improved treatment strategies. This review aims to offer some practical

guidelines for pathologists, pointing out pitfalls along the way.

Keywords pathology; pulmonary arterial hypertension; pulmonary

artery; pulmonary hypertension

Introduction

Pulmonary hypertension (PH), i.e. a pathologically elevated

pulmonary artery pressure, occurs in a group of diseases and

syndromes with various etiologies and risk factors. The under-

lying increased resistance of the pulmonary vasculature is due to

vasoconstriction (with or without increased vascular respon-

siveness), vascular remodelling, or a combination of the two.

Although initially, even remodelling is reversible to some extent,

the PH itself may eventually become self-perpetuating and pro-

gressive, resulting in a dire prognosis, mainly due to cardiaccomplications including right ventricular failure.1

The sporadic idiopathic or hereditary forms of PH are rare. PH

per se, however, is not so rare, since several common diseases

may cause, or contribute to, PH: left ventricular failure and mitral

valve insufficiency, chronic thromboembolic disease, collagen

vascular diseases, fibrosing lung diseases, HIV-AIDS and, in

endemic areas, sickle cell disease and chronic schistosomiasis

(Table 1). The clinical classification of PH is largely based on

(clusters of) these etiologies and risk factors.1

The wide variety of causes and risk factors of PH indicates that

different pathogenetic pathways are operative. Once PH is estab-

lished, hypertension itself comes to act as a stress factor on the

vasculature by way of shear stress. Thus, in addition to pathoge-netic pathways related to its cause, PH itself drives the pathogenesis

of pulmonary vascular damage; a notion supported by the partly

overlapping, partly distinctive patterns of vasculopathy in PH.

While histopathological evaluation has long been the basis of

classification, surgical lung biopsy is a high risk procedure in PH.

Therefore, the role for histopathological evaluation has in part

shifted to retrospective evaluation on explanted lung or tissue

obtained at autopsy, in favour of a clinical classification,1 in

which categories are mainly defined by clinical behaviour and

response to treatment. However, histological evaluation, taking

clinical work-up, including haemodynamic parameters and HRCT

imaging, into account in a multidisciplinary setting may help

assess the prognosis, including risk of recurrence in a transplant,and possible risk of PH in family members. More generally,

systematic evaluation may identify clues as to pathogenesis and

may help to fill the knowledge gap between histopathology and

non-invasive diagnostic procedures such as imaging. This will

hopefully eventually lead to a pathophysiologic rational for

classification, and improved treatment strategies.

This review aims to offer some practical guidelines for pa-

thologists having to recognize and classify pulmonary vascular

disease, pointing out pitfalls along the way, so as to avoid vague

and all-encompassing diagnosis of vasculopathy in the spec-

trum of hypertensive vascular disease, which obscures key

distinctions regarding classification of PH, and impedes eluci-

dation of the various pathogenetic mechanisms.

Minimum tissue requirements

The lung owes its volume mainly to air. Collapse of lung tissue

compromises the assessment of many histological features, and

may be avoided by infusing the tissue with formalin and allowing

it to fix before cutting.2 The infusion can simply be done by fine

needle and syringe, through the pleura. It should be done gently,

to avoid washing out diagnostic macrophages and side-

rophages, and also to avoid artifacts that mimic oedema or

lymphangiectasis.

For proper evaluation of the pulmonary blood vessels, an

additional elastin stain, such as Elastic van Gieson (EvG), Mas-

son trichrome combined with an elastin stain, or Movat pen-

tachrome stain, is indispensable.3e5 To avoid overlooking mild

hemosiderosis, an iron stain is recommended.3e5

Pathogenesis: hypoxia and shear stress

Pulmonary hypertension is a multi-factorial condition and pul-

monary vascular disease is shaped by the combined action of

genetic, epigenetic and immune-related factors (reviewed by

Rabinovitch6 and El Chami7). In the plethora of pathogenetic

mechanisms described in PH, two major mechanisms stand out,

namely, hypoxia and shear stress. Little is know about endoge-

nous neural regulation of vascular tone.

Katrien Grunberg MD PhD Department of Pathology, VU Medical Center,

Amsterdam, The Netherlands. Conflicts of interest: none declared.

Wolter J MooiMD PhD Department of Pathology, VU Medical Center,

Amsterdam, The Netherlands. Conflicts of interest: none declared.

MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

DIAGNOSTIC HISTOPATHOLOGY 19:8 298 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.mpdhp.2013.06.013http://dx.doi.org/10.1016/j.mpdhp.2013.06.013


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Hypoxia

In the pulmonary circulation, hypoxia is a potent vasocon-

strictor. Acute hypoxic vasoconstriction is reversible, allowing

continuous optimization of ventilation-perfusion ratio. Chronic

hypoxia, however, may eventually increase PVR in part by

inducing vascular remodelling. PH in high-altitude dwellers is

hypoxia-driven PH in its pure form. In PH of various other cau-

ses, hypoxia contributes to increased PVR post aut propter

(reviewed by Voelkel et al8).

Shear stress

The second trigger for vascular remodelling is shear stress. Shear

stress is evoked by chronic hyperflow conditions, such as in left-

to-right intracardiac shunting (see also section risk factors). In

the course of the disease, as some vessels become occluded,

hyperflow ensues in the vessels that are still patent, resulting in

secondary shear stress. Shear stress is most severe just beyond

any branching point or partial obstruction, where laminar flowconverts to turbulent flow. Shear stress evokes vasoconstriction

by regulating the release of various potent vasoconstrictors from

the endothelium, such as endothelin, or lack of those, such as

reduced nitric oxide production. Shear stress also initiates

endothelium-driven remodelling, involving clotting, inflamma-

tion, and post-thrombotic intimal fibrosis. The mechanisms

operative in vascular remodelling involve the BMPR2-TGF-beta

signalling pathway, serotonin signalling, and inflammation, in

which IL-6 is a central mediator and several chemokines have

been implicated.

Risk factors

Risk factors (Table 2) can be categorized by pathogeneticmechanism. The first category of conditions is associated with

abnormally increased flow of blood through the lung. Among

these are intracardiac left-to-right shunting (particularly post-

tricuspid shunting such as in VSD), systemic A-V shunts as in

A-V malformations, or iatrogenic A-V shunts for haemodialysis.

Second are drugs, diseases, or genetic mutations that interfere

with the BMPR-2-TGF-beta signalling pathway and/or serotonin

signalling, or cellular immunity. Most clearly implicated are

appetite-suppressants belonging to the class of serotonin-

reuptake inhibitors. Hereditary forms of PH often have muta-

tions in one of these pathways, and most often concern the

BMPR-2 gene.

Third are conditions associated with chronic hypoxia. Beside

living at high altitude, alveolar hypoventilation (as in sleep

apnoea syndrome, morbid obesity) can cause hypoxia-driven PH.

Hypoxia may complicate destructive lung diseases such as

fibrosing interstitial lung disease and COPD. It should be noted

that hypoxia is particularly prominent in PH from post-capillary

obstruction of any cause. However, it is uncertain whether

hypoxia is the driving mechanism of vasoconstriction and/or

vascular remodelling in these diseases.9

Fourth are pulmonary emboli, either or not associated with a

pro-thrombotic predisposition. Beside thrombo-emboli, emboli

from other sources should be taken into consideration, such as

tumour emboli, or parasites (e.g. Schistosoma eggs). In situ

thrombosis and post-thrombotic remodelling may complicate

any form of PH.

Finally, there is a waste basket category in which for

example Gauchers disease is placed, together with sarcoidosis.

The mechanisms of vascular disease in this category is diverse,

and sometimes unknown.

Pulmonary vasculopathy in PH: general features

Pulmonary arterial remodelling, particularly of axial vessels

(i.e. those running along airways) is a general feature of most

cases of PH. An early and constant feature is medial hyperpla-

sia. The media is thickened when it exceeds 7% of the arterial

Risk factors and associated conditions for PAH(adapted from Ref.1,62)

A. Drugs and toxins

1. Definite

C Aminorex (Menocil)

C

Fenfluramine (Ponderal)C Dexfenfluramine (Adifax, Redux)C Fenfluramine-phentermine

C Toxic rape seed oil

2. Likely

C Amphetamines

C Metamphetamines

C L-tryptophan

3. Possible

C Cocaine

C Chemotherapeutic agentsC PhenylpropanolamineC

Hypericum perforatum (a.k.a. St. Johns Wort, Tiptons weed orKlamath weed, a herbal treatment for depression)

C Selective serotonin reuptake inhibitors (SSRI)

B. DiseasesC HIV infection

C Portal hypertension/liver disease

C Collagen vascular diseases

C Congenital or acquired systemic-pulmonary-cardiac shunts (left-

to-right shunts)

Atrial and/or ventricular septal defect

Transposition of the great arteries with VSD

Truncus arteriosus persistens

Patent ductus arteriosus

Aorto-pulmonary window Surgical shunt for tetralogy of Fallot

PossibleC Thyroid disorders

C. Genetic predispositions: genes involvedC BMPR2

C ALK-1(with or without clinically overt HHTa)

C Endoglin

C TGF-bC SMADs

a Hemorrhagic hereditary teleangiectasia, Rendu-Osler Webers disease.

Table 1




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Dana Point clinical classification of pulmonary hypertension (2008)1 vis-a-vis histopathological patterns of pulmonaryhypertensive disease5

Dana point clinical classification 2008 Histopathological pattern

1. Pulmonary arterial hypertension (PAH)

1.1. Idiopathic PAH PPA

1.2. Hereditary

1.2.1. BMPR2 PPA/PVOD

1.2.2. ALK1, endoglin PPA

1.2.3. Unknown PPA/PVOD

1.3. Drug- and toxin-induced PPAa

1.4. Associated with

1.4.1. Connective tissue diseases PPA/PVOD/SSc/congestive

1.4.2. HIV infection PPA

1.4.3. Portal hypertension PPA

1.4.4. Congenital heart diseases PPA

1.4.5. Schistosomiasis PPA/thrombotic

1.4.6. Chronic haemolytic anaemia PPA/thromboticb

1.5 Persistent pulmonary hypertension of the newborn Various, depending on cause

10 Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary

haemangiomatosis (PCH)

PVOD

2. Pulmonary hypertension owing to left heart disease

2.1. Systolic dysfunction Congestive

2.2. Diastolic dysfunction Congestive

2.3. Valvular disease Congestive

3. Pulmonary hypertension owing to lung diseases and/or hypoxia

3.1. Chronic obstructive pulmonary disease Hypoxic

3.2. Interstitial lung disease Hypoxic/thromboticc

3.3. Other pulmonary diseases with mixed restrictive and obstructive pattern Hypoxic/thrombotic

3.4. Sleep-disordered breathing Hypoxic

3.5. Alveolar hypoventilation disorders Hypoxic

3.6. Chronic exposure to high altitude Hypoxic

3.7. Developmental abnormalities Hypoxic (see also 1.5)

4. Chronic thromboembolic pulmonary hypertension (CTEPH) Thrombotic

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1. Haematologic disorders: myeloproliferative disorders, splenectomy Thrombotic arteriopathy, vascular

occlusion by leukaemic cells

5.2. Systemic disorders:

Sarcoidosis Thrombotic/Hypoxic/Congestive

Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis Thrombotic

Vasculitis Thrombotic

5.3. Metabolic disorders: glycogen storage disease, thyroid disorders

Gauchers disease PPA

5.4. Others:

Tumoral obstruction Thrombotic, embolic

Fibrosing mediastinitis Congestive

Chronic renal failure on dialysis PVODd

PPA plexogenic pulmonary arteriopathy; ALK1 activin receptor-like kinase type 1; BMPR2 bone morphogenetic protein receptor type 2; HIV human immuno-

deficiency virus.a In drugs causing rise in serotonin levels, such as appetite suppressants, amphetamines, antidepressants.b In sickle cell disease: thrombotic arteriopathy.c Post-thrombotic remodelling or endarteritis obliteransd Own anecdotal observation.

Table 2




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diameter as measured at the outer elastic lamina. When

assessing media hyperplasia, the vessel calibre should be taken

into account. The calibre, normally about one third to half the

diameter of the accompanying airway, is often increased in PH.

However, as vessel and airway calibre are subject to variable

post-operation/mortem rigour, this parameter can hardly be

quantified reliably. Exception to the rule of generalized medial

hyperplasia is chronic thrombo-embolic pulmonary hyperten-sion (CTEPH), where the degree of remodelling may vary

greatly among pulmonary arteries, leaving some areas seem-

ingly unaffected.

The second general feature is pulmonary artery intimal

fibrosis. Subendothelial intimal cells may show myofibroblastic

differentiation,10 which no doubt have an impact on the vessel

wall functional properties.11 In the large, elastic arteries this may

present as atherosclerotic plaques.

There is one specific type of intimal fibrosis, concentric laminar

intimal fibrosis, which has been considered suggestive of plexo-

genic arteriopathy.4,5 Concentric layering of collagen and myofi-

broblasts within small arteries is evident on H&E stained sections,

also referred to as onion skin fibrosis (Figure 1). In a more recentstudy, concentric laminar intimal fibrosis was found to be espe-

cially prominent in systemic sclerosis-associated PH, and less so in

plexogenic arteriopathy.12 It is as yet uncertain as to whether this

type of intimal fibrosis has distinctive pathogenetic relevance

when compared to garden-variety concentric intimal fibrosis.

Concentric laminar intimal fibrosis may evolve to a new muscular

media around a residual lumen, sometimes with newly formed

elastin on either side, thus mimicking the media of a muscular

pulmonary artery. Such a double media is another characteristic

feature of systemic sclerosis associated PAH.

Pulmonary vasculopathy: patterns & pitfalls

Pattern 1: plexogenic arteriopathyIntroduction:plexogenic arteriopathy is found in PAH in group 1,

and has been described in a case of Gauchers disease.13 The

plexiform lesion, to be described in detail below, is pathognomonic

for this pattern. It is considered to indicate late phase and self-

perpetuating disease.10,14 Plexiform lesions are not a feature of

diseases in groups 2e5.1

PAH affects women two to three times more often than men15.

Plexogenic arteriopathy may be familial, or associated with a va-

riety of conditions (Table 3). Congenital post-tricuspid left-to-right

shunt is a major risk factor. Progression to Eisenmengers syn-

drome (reversal of the direction of blood flow across the shunt,resulting in systemic hypoxaemia and hypercapnia) may ensue,

unless early surgical correction is carried out4,5. Other, minor risk

factors include portal hypertension of any cause, various germline

mutations (e.g. inBMPR2), hemorrhagic hereditary telangiectasia

(HHT, Rendu-Osler disease), SLE, and HIV infection (see Dana

Point classification 2008 group 1, see Table 1).1 Serotonin re-

uptake inhibitor drugs, particularly those with appetitee

suppressant activity, have been recognized since the late 1960s as

a risk factor.1 Chronic Schistosoma infection, particularly

S. mansoni, is a minor risk factor for PH, yet with major impact

due to the high global prevalence of this infectious disease.

Endemic areas include the north-west of South America, parts of

the Caribbean, and North-East Africa.16

Embolizing schistosomaeggs may cause thromboembolic lesions.17 However, nowadays

PH in chronic schistosomiasis appears to feature plexogenic

arteriopathy rather than thrombotic arteriopathy, in line with the

presence of pipestem liver cirrhosis in all such cases5,17.

Histopathology of plexogenic arteriopathy:the general features

of PH also apply to plexogenic arteriopathy. In the earliest stages

of the disease, medial hyperplasia of elastic and muscular ar-

teries is a constant e and often the only e abnormality.4,5,10 In

addition, there may be variable amount of intimal fibrosis.5,10,18

The plexiform lesion (Figure 2), pathognomonic for this

pattern, usually involves a supernumerary arterycloseto itsorigin

from the axial parent vessel.

19

The lesion consists of a plexus ofslit-like or wider channels lined by small, flat or slightly plump

endothelial cells and subjacent myofibroblasts. The lesion is

commonly surrounded by one or several markedly dilated vein-

like arterial branches.18,20 When such dilatation lesions occur

in isolation, or in clusters without the associated plexus, they are

referred to as angiomatoid lesions.21 The parent axial artery

commonly exhibits focal intimal fibrosis near the origin of the

supernumerary artery. The affected supernumerary artery may

display a small area of fibrinoid necrosis, mostcommonlybetween

its origo and the plexus of vascular lumina20. Affected arterials

segments show intense eosinophilia and apparent loss of nuclei in

H&E-stained sections. There may be associated thrombus within

the lumen of the affected branch. Fibrin and/or thrombus arecommonly present, either within the parent vessel or as small

deposits within the plexus22 (Figure 2a). The formation of plexi-

form lesions is considered to be a late phase event in the course of

the disease. Hence its name plexogenic arteriopathy (originally

intended to mean an arteriopathy that, in the course of its pro-

gression, generates the formation of plexiform lesions), implying

that it can be diagnosed in the absence of plexiform lesions, when

there is distinct concentric fibrosis or angiomatoid lesions, fibri-

noid necrosis in proximal segments of supernumerary arteries or,

preferably, a combination of these findings.

Focal arteritis is rare, and manifests as a transmural round-cell

inflammatory infiltrate, most commonly affecting an axial

Figure 1Concentric intimal fibrosis. Example of concentric laminar intimafibrosis in elastin von Gieson staining. The concentric, cellular aspect of

this type may well be appreciated in HE stain.




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muscular pulmonary artery. It may be accompanied by fibrinoid

necrosis. Such necrotizing arteritis may be seen in severe

advanced plexogenic arteriopathy, and probably represents a

consequence rather than a cause of the hypertension. SeeTables 3

and4for summary of clues and a simple algorithm.

Pitfall 1

Plexogenic arteriopathy vs thrombotic arteriopathy: plexiformlesionsare not a feature of severe hypoxic PH, congestive vas-

culopathy, or PVOD. Despite claims to the contrary, the plexiform

lesion can and should be distinguished from the commoner

organizing thrombus or thrombo-embolus.22 The histopatholog-

ical patterns differ. The plexus in plexiform lesions may be remi-

niscent of and organizing thrombus (especially when fibrin or

fresh thrombus is present). However, unlike organizing thrombi,

plexiform lesions are typically situated in a supernumerary artery,

close to its origin, and they are surrounded by dilatation lesions.

That having been said, occasional post-thrombotic lesions may be

encountered in all types of pulmonary hypertensive vascular dis-

ease, including plexogenic arteriopathy. Therefore, the finding of

Clues to diagnosis of pattern of vasculopathy. In the tablebelow, the diagnostic clues to 6 patterns of pulmonary

vasculopathy have been graded according to specificity,ranging from 1 (highly specific) to 3 (low specificity). Asa rule of thumb, to diagnose a specific pattern, at leastone clue from category 1 should be present. The

algorithm inTable 4describes a simple diagnosticapproach; a guide through seemingly similar patterns

Category Type

Clues to plexogenic arteriopathy3e5

1 Plexiform lesions

1 Dilatation lesions, including angiomatoid lesions

2 Focal pulmonary arterial fibrinoid necrosis

2 Necrotizing arteritis (occasionally in severe, advanced

disease).

3 Arterial medial hyperplasia

3 Cellular intimal proliferation

3 Tortuosity of pulmonary arteries

3 Concentric laminar intimal fibrosis

Clues to thrombotic arteriopathy4,5

1 Intravascular fibrous septa (webs and bands), colander

lesions

1 Recent thrombi (usually rare or absent) or re-canalizing

thrombi (uncommon)

2 Eccentric, irregular intimal fibrosis

2 Medial hyperplasia of muscular pulmonary arteries:

mild or absent

Clues to hypoxic arteriopathy

2 Medial hyperplasia, especially of small muscular

pulmonary arteries1 Muscularization of arterioles

1 Intimal longitudinal smooth muscle bundles in small

arteries and in arterioles

2 Arterial adventitial thickening

2 Mild increase in venous smooth muscle

3 Intimal fibro-elastosis

Clues to congestive arteriopathy

Pulmonary veins:

1 Medial hypertrophy and arterialization

2 Mild to moderate intimal fibrosis

Pulmonary arteries:

2 Prominent medial hyperplasia of muscular pulmonaryarteries and muscularization of arterioles

2 Marked adventitial thickening

Lymphatics

1 Dilatation

Lung tissue

2 Alveolar oedema

2 Interstitial fibrosis (alveolar septa, non-destructive,

patchy or confluent)

2 Hemosiderosis

1 Interstitial iron deposition and/or

pseudopneumoconiosis

Table 3 (continued)

Category Type

1 Microlithiasis, osseous nodules (rare)

Clues to PVOD/PCH

Pulmonary veins and venules

1 Focal obstructive intimal fibrosis, initially of loosetexture, within venules and small, pre-septal veins.

Pulmonary arteries

2 Medial hyperplasia

2 Adventitial fibrosis

Lymphatics

2 Dilatation

2 Fibrotic thickening of interlobular septa

Lung tissue

1 Patchy congestion, evolving to focal interstitial fibrosis

2 Prominent focal hemosiderosis,

pseudopneumoconiosis

Clues to systemic sclerosis-associated vasculopathyPulmonary arteries

3 Media hyperplasia

2 Generalized intimal fibrosis, extending into

parenchymal arterioles (common)

1 Smooth muscle or densely collagenous subintimal

fibrotic rim in corner vessels

1 Concentric laminar intimal fibrosis (occasional)

Venules

2 PVOD-like changes (occasionally): focal venular intimal

fibrosis associated with patchy congestion and

hemosiderosis

Lung tissue

2 Interstitial fibrosis (NSIP pattern and/or congestivepattern)

Table 3




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an obvious post-thrombotic lesion does not indicate thrombotic

arteriopathy as a single pattern, or exclude plexogenic

arteriopathy.

Pattern 2: thrombotic arteriopathy

Introduction: theVirchows triad of injury to endothelium, al-

terations in normal blood flow and hypercoagulability of the

blood still holds as contributors to thrombosis, and hence,

thrombotic arteriopathy. Specific conditions are listed inTable 5.

CTEPH is clinically defined as PH after acute pulmonary

thrombo-embolism. It usually arises within the first two years

Figure 2Three examples of plexiform lesions. (a) Plexiform lesion positioned inside and adjacent to a pulmonary artery. (b) Plexiform lesion with typicalglomeruloid appearance, featuring a central lesion with slit-like vessels, lined with rather cuboidal-looking endothelium, and surrounded by vein-like

branches. (c) Plexiform lesion positioned just adjacent to a pulmonary artery, consisting of a small glomeruloid lesion, and several, prominent vein-likebranches.

A simple algorithm

Step 1: Plexiform lesions, angiomatoid lesions present?

Yes: plexogenic arteriopathy (check for combined patterns, un-

derlying disease)

No: check for venous/venular changes

Step 2: Veins/venules affected and/or interstitial hemosiderosis

(pseudopneumoconiosis)?

Yes: differential diagnosis of congestive vasculopathy vs PVOD

No: possible thrombotic, hypoxic, or early stage plexogenic

arteriopathy

Step 3: Arteriolar muscularisation present?

Yes: hypoxic arteriopathy (check for combined patterns, underly-

ing disease)

No: possible thrombotic arteriopathy (sample thoroughly, check

for webs, colander lesions)

Step 4:

Infarcts present?

Yes: consider combined congestive and thrombotic

Note 1: combinations of patterns may occur, such as thrombotic conges-

tive, hypoxic congestive (or any other).

Note 2: the distinction between congestive vasculopathy and PVOD may be

difficult or impossible. In those cases, a diagnosis may be reached in multi-

disciplinary approach, taking wedge pressure and clinical information into ac-

count.

Table 4

Long term risk factors of pulmonary thromboembolism

C Deficiency of antithrombin, protein C, protein S, Factor V Leiden,

prothrombin G20210A mutation

C Two or more first-degree relatives with venousthromboembolism

C Lupus anticoagulant, anticardiolipin/antiphospholipid

antibodies

C Malignancy, especially adenocarcinomas of stomach, pancreas

and ovary

C Immobilization from chronic disease

C Sickle cell disease

C B thalassaemia

C Asplenic state

C Blood group non-0

Table 5




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after the initial thromboembolic event, but the symptom-free

interval may be longer.23 In about 30% of CTEPH patients

there is no documented acute thromboembolic episode24; this

situation is known as silent recurrent pulmonary thromboem-

bolism. CTEPH is classified in group 4 of the Dana Point clas-

sification 2008.1

Histopathology of thrombotic arteriopathy: thrombotic occlu-sion of a pulmonary artery may result from thrombo-embolism,

primary thrombosis, or a combination of both. Generally,

thrombo-emboli tend to affect the larger vessels (Figure 3), while

in situ thrombosis affects smaller vessels, but they cannot be

distinguished reliably by histology. The term thrombotic arte-

riopathy conveniently covers both entities.4,5 In spite of what

the name suggests, thrombi are rarely a feature of thrombotic

arteriopathy. Thrombi or thrombo-emboli are quickly resolved or

organized and replaced by scar tissue, recognizable as eccentric

intimal fibrosis, intravascular webs and bands, or colander-

lesions4,5,25 (Figure 4). In large arteries, collections of foamy

histiocytes and/or cholesterol clefts are common in or near

organized thrombi, and calcification is occasionally seen.25 Le-

sions usually affect only a small segment of a vessel, leaving the

remaining stretch unaffected (or even protected). Hence,

vascular lesions in thrombotic arteriopathy in CTEPH can be

notoriously inconspicuous and unevenly distributed.20,26

Post-thrombotic lesions can be recognized as early-late orga-

nizing phase. However, experimental data supporting reliablecorrelation the various stages of organization with the age of the

thrombus are largely lacking. The media and adventitia of a

thrombosed artery are usually unremarkable. There may be

slight medial hypertrophy or atrophy, but the changes are usually

mild.

List of Abbreviations and glossary of terms

ALK1 Activin receptor-like kinase type I

BMPR2 Bone morphogenetic protein receptor type II

CTEPH Chronic thrombo-embolic pulmonary hypertension

iPAH Idiopathic pulmonary arterial hypertension

PAH Pulmonary arterial hypertension (prefix i for

idiopathic). PAH is in group 1 (Dana point)1

PCH Pulmonary capillary haemangiomatosis

PH Pulmonary hypertension

PVOD Pulmonary veno-occlusive disease

SMAD Transcription factor, human homologue of both

the drosophila protein MAD and the C. elegans

protein, SMA

SSc Limited cutaneous form of systemic sclerosis

TGF-b Transforming growth factor-b

PA Pulmonary artery

HHT Hemorrhagic hereditary teleangiectasia (m. Rendu

Osler Weber)

PAP Pulmonary artery pressure. PAP is measured by

right heart catheterization, or estimated by

cardiac ultrasound.

PGI2 Prostacyclin (epoprostanol, flolan). A vasodilator

drug administered by continuous i.v. infusion.

PH non PAH Pulmonary hypertension, not belonging to the

group 1 of pulmonary arterial hypertension.1

Formerly known as secondary pulmonary

hypertension.

PVR Pulmonary vascular resistance

SCD Sickle cell disease

Wedge

pressure

Measured by wedging a pressure catheter in a

small pulmonary artery, thereby estimating the

capillary and venous pressure. Is elevated in

venous outflow obstruction, e.g. in left heart

failure, mitral valve insufficiency

Table 6

Figure 3 Gross pathology of several thrombo-emboli in the pulmonaryarteries. Note the red-and-white layering of the thrombi.

Figure 4Thrombotic arteriopathy. Colander lesion; partly recanalized andpartly fibrotic post-thrombotic scar, reminiscent of a sieve or colander.




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Pitfall 2

Infarcts point towards combined pattern of thrombotic andcongestive vasculopathy:ventilation of the lungs and their dual

blood supply are usually sufficient to prevent parenchymal

infarction from pulmonary artery occlusion. However, when

blood flow stagnates due to congestion, conditions for pulmo-

nary infarction (Figure 5) are met. Congestive pulmonary vas-

culopathy is often complicated by arterial thrombosis, and

pulmonary infarcts are characteristic of that combination.4,5 In-

farcts are typically pleura-based and wedge-shaped. Initially, the

infarcted lung tissue is hemorrhagic (Figure 5a). Gradually,

epithelial and endothelial cell nuclei disappear while elastic

fragments remain, raising the impression of elastosis (Figure 5b).

Organization starts at the periphery. Granulation tissue and

hemosiderin-laden macrophages replace the necrotic tissue andfill up alveolar spaces. Overlying pleura becomes thickened and

inflamed. Squamous metaplasia and endarteritis obliterans may

be noted. Infection, for example from infective thrombophlebitis,

catheters or right heart valve endocarditis, may complicate the

healing of infarction,27 and cavitation or abscess formation may

ensue.

Pattern 3 hypoxic arteriopathy

Introduction: hypoxic arteriopathy (Dana Point classification2008 group 31) in its pure form is found in people living at high

altitudes, as in the high Andes and Himalayas.4,5 Closer to sea

level, hypoxic arteriopathy may complicate chronic lung disease

with a reduced diffusion capacity, such as COPD and fibrotic lung

diseases.4,5,28 Alveolar hypoventilation, as occurs in sleep

apnoea syndrome and morbid obesity, is also a well-known risk

factor for hypoxic arteriopathy.1,29 It should be noted that hyp-

oxia with reduced diffusion capacity is often a prominent feature

of congestive vasculopathy30 and PVOD.

Histopathology of hypoxic arteriopathy: hallmarks of hypoxic

remodelling are medial hyperplasia of pulmonary arteries, espe-

cially of small branches (Figure 6a,b). Also, arterioles normallydevoid of a muscular coat, develop a distinct muscular media,

sandwiched between inner and outer elastic laminae (so-called

muscularization of arterioles).4,28 Small, longitudinally arranged

bundles of smooth muscle lined by elastin fibres may be found in

the intima of arteries and arterioles (Figure 6b). This feature is

suggestive, but not pathognomonic, of hypoxic arteriopathy, as it

Figure 5Pulmonary infarct. (a) Recent pulmonary infarction with hemorrhagic aspect. Note the thrombosis in one of the vessels in the top op the pyramidshape. (b) organized and fibrotic subpleural microinfarct. Note the elastotic remnants of the alveolar septa, and fibrotic filling of the former alveolarspaces.

Figure 6Hypoxic arteriopathy. (a) Axial pulmonary artery with media hyperplasia. Note the prominent collagenous adventitia, common in both congestivearteriopathy and hypoxic arteriopathy. (b) Muscularized pulmonary arteriole; a corner vessel in the alveolar parenchyma, positioned at the intersection ofalveolar attachments. Arterioles at this terminal level should be devoid of muscular media. Muscularization points towards hypoxia. Note the bumps in

the intima, lined with elastin fibres. These are longitudinal smooth muscle bundles, and are also characteristic of hypoxic remodelling.




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may be encountered in other conditions, and may affect the larger

pulmonary, bronchial and systemic arteries, particularly when

there is extensive vascular smooth muscle hyperplasia.4,5 Finally,

adventitial thickening of the pulmonary arteries may be observed

in hypoxic pulmonary vasculopathy5 (Figure 6a). In adults, the

arterial adventitia is normally inconspicuous. Adventitial thick-

ening was originally described as a feature of congestive vascul-

opathy, but it is also a consistent finding in animal models ofhypoxic arteriopathy (reviewed by Stenmark31). Intriguingly,

congestive vasculopathy is often associated with low diffusion

capacity, and hence, hypoxia. A slight increase in pulmonary

venous and venular smooth muscle has been described, but not

full blown arterialization as occurs in congestive vasculopathy

(see below).4,5 The histopathological characteristics of hypoxic

arteriopathy as we know them, come from studies in humans (or

animals) exposed to low ambient air oxygen. It is as yet uncertain

if and how this is representative of PH in hypoxia due to disease-

associated low diffusion capacity.

Pattern 4 congestive vasculopathy

Chronic elevation of the pulmonary venous blood pressure,regardless of its cause, results in congestive pulmonary vascul-

opathy.4,5 It may result from outflow obstruction at the hilar,

mediastinal level (for example by fibrosing mediastinitis), or

from left atrial tumour (Dana Point classification 2008 group 51).

Most cases however result from left ventricular failure or mitral

valve insufficiency (Dana Point classification 2008 group 21).

Indeed, left ventricular failure and mitral valve disease are

among the major causes of non-PAH PH (formerly known as

secondary PH).30 The outflow obstruction is reflected by an

elevated wedge pressure (>15 mmHg) at right heart catheteri-

zation. This finding excludes pulmonary arterial hypertension

(Dana Point classification 2008 group 11) as a single diagnosis.

Congestive pulmonary vasculopathy due to mitral valve insuffi-ciency often regresses significantly after valvular surgery.

Histopathology of congestive vasculopathy: arterialization of

veins is the most distinctive feature in congestive pulmonary

vasculopathy4,5 (Figure 7a). Arterialized veins come to resemble

muscular pulmonary arteries as they acquire distinct inner and

outer elastic laminae sandwiching a compact layer of medial

smooth muscle. Such arterialized veins may be difficult to

distinguish from pulmonary arteries by morphology alone. Their

identity is revealed by their localization in the interlobular septa.

The rise in pulmonary arterial pressure usually exceeds that of

the venous pressure, pointing towards associated pulmonary

artery vasoconstriction.32 This is parallelled by prominent pul-

monary arterials medial hyperplasia.32

Characteristically, there isalso substantial thickening of the arterial adventitia.4,5

Secondaryfindings of chronic congestion include intra-alveolar

oedema, dilatation of lymphatics (Figure 7a), interstitial oedema,

and relatively diffuse fibrosis of the alveolar interstitium without

architectural distortion. Increased numbers of mast cells are seen.

Intra-alveolar calcification and/or focal ossification may arise.

Congestion is associated with the presence of siderophages,

interstitial iron deposition, and focal encrustation of venous

elastin fibres by iron salts33 (Figure 7b). Even subtle interstitial

iron deposition forms an important diagnostic clue, so that an iron

stain is required in order not to overlook it. When severe, iron

pigmentation in association with the diffuse fibrosis results in so-

called brown induration of the lung by its macroscopicappearance.

Pattern 5: pulmonary veno-occlusive disease (PVOD) and

pulmonary capillary haemangiomatosis (PCH)

Introduction: PVOD and PCH are rare34 but severe and often

rapidly progressive pulmonary hypertensive diseases,35,36 char-

acterized by a decreased diffusion capacity, out of proportion to a

relatively mild elevation of pulmonary arterial pressure. Patients

may have (occult) alveolar haemorrhage. The diagnose is based

on the distinctive histopathological pattern of vascular disease.

Prognosis is generally worse than other PAH entities of group 1.

Hence, its classification as a separate entity, as group 1 0 of the

Dana Point classification 2008.

1

Vasodilator drugs such as pros-tacyclin are usually less effective than in other types of PAH, and

may cause acute pulmonary oedema.36 At present, the only

effective treatment is lung transplantation, but preliminary evi-

dence suggests a possible beneficial effect of imatinib (STI571), a

PDGFR tyrosine kinase inhibitor (e.g.37). Case reports indicate

possible occurrence38 or recurrence39 in a bilateral lung

Figure 7 Congestive vasculopathy. (a) Arterialized vein, localized in an interlobular septum. The vein shows a distinct media. Unlike pulmonary arteries,the elastin layers are slightly disorderly. Note the prominent lymphangiectases, also in the septum. (b) Interstitial iron depositions on vascular elastinfibres. Interstitial iron deposition (Perls iron) is a feature of congestion, regardless of its cause, and may be seen in PVOD as well as congestive vas-

culopathy. While interstitial iron is highly specific for congestion, the presence of hemosiderophages may indicate either congestion or alveolar hae-

morrhage of other causes. Note the marked iron encrustation of the vascular elastin fibres.




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transplant. PVOD, or a pattern of vascular lesions closely

resembling it, complicates a number of connective tissue dis-

eases, particularly systemic sclerosis/CREST syndrome and, oc-

casionally, SLE. An association has also been found with

autoimmune thyroid disease, and Raynauds phenomenon often

precedes the development of PVOD. PVOD may develop as a late

complication of radiotherapy, especially for Hodgkin lym-

phoma.40

Some chemotherapeutic agents, including BCNU,bleomycin, and mitomycin41 have also been incriminated, as

have bone marrow or stem cell transplantation,42e44 and heart

and/or lung transplantation. Finally, PVOD has been reported to

occur as a familial disease45 and BMPR2 mutations have been

identified in several cases.36,46,47

Of note, elevated wedge pressure is not a feature of PVOD/

PCH.

Because of the great resemblance of PVOD and PCH, the two

together being distinct from all other patterns (except congestive

vasculopathy is some respects), PCH and PVOD are discussed

together here.

Radiological features of PVOD/PCH: high resolution computedtomography (HRCT) of the chest is highly useful in the diagnosis

of PVOD/PCHvs other forms of PAH and CTEPH. Beside general

features of PH and possible underlying disease, it may demon-

strate features characteristic of PVOD.47 These include diffusely

distributed centrilobular ground-glass opacities, and subpleural

septal lines, so-called Kerley B lines. Mediastinal lymph node

enlargement may be prominent. Pleural and/or pericardial effu-

sions do not discriminate between PVOD/PCH and other types of

PAH or CTEPH.

Histopathology of pulmonary veno-occlusive disease (PVOD)

and capillary haemangiomatosis (PCH): PVOD/PCH is charac-

terized by a focal progressive fibrotic stenosis and obliteration of

venules and small veins (Figure 8a,b). This fibrotic obliteration is

characteristically loosely textured.48 Web lesions may be found in

veins and venules. Significantly, larger (interlobular) veins are

normal or near-normal, and there is no arterialization as in

congestive vasculopathy. The localized obstruction is associatedwith intense congestion of the lung parenchyma surrounding the

affected vessel(s) (Figure 8a,c). This may be patchy (and well-

demarcated), or occasionally confluent.4,5,48 In some areas or

cases, the widely patent capillaries may result in a strikingly

densely crowded appearance within alveolar walls and the inter-

stitium of bronchovascular bundles.4,5,49 The term pulmonary

capillary haemangiomatosis (PCH) was originally applied to such

cases.4,5 Bleeding from the engorged capillaries may lead to hae-

moptysis, hemosiderin deposition, typicallyin the periphery of the

secondary lobule (i.e.beneath the visceral pleura and interlobular

septa). As in congestive vasculopathy, calcium and iron salt

encrustation of venular and alveolar wall elastic fibres may cause

a giant cell response, sometimes referred to as pseudo-pneumoconiosis or endogenous pneumoconiosis33 (Figure 7b).

Occasionally small arteries and arterioles also display intimal

fibrosis, but to a far lesser degree than that seen in venules. The

termvaso-occlusive has been proposed for those cases in which

both venular and arterial/arteriolar intimal fibrosis is marked.50

When checking for underlying interstitial lung disease, one

should bare in mind that interstitial fibrosis may ensue from

long-standing congestion itself, and hence, may be a conse-

quence rather than a cause.

Figure 8 Pulmonary veno-occlusive disease (PVOD). (a) A well-demarcated area of capillary congestion (patchy congestion), in otherwise normal lungtissue. (b) loose concentric venular intimal fibrosis in area of capillary congestion. (c) Interstitial fibrosis without architectural destruction in chroniccongestion in long standing PVOD (explanted lung, PVOD confirmed in previous biopsy).




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Pitfall 3: PVODvs congestive vasculopathy

There is some histologic overlap between congestive vasculop-

athy and PVOD/PCH. Congestive vasculopathy is the proverbial

garden variety, PVOD/PCH a rare hybrid. A diagnosis of PVOD/

PCH should therefore be made reluctantly, and only after careful

evaluation of clinical information, haemodynamic parameters

(notably wedge pressure) and HR-CT scan findings to exclude

possible causes for congestive vasculopathy.Generally, congestion in congestive vasculopathy tends to

affect the basal areas more prominently, and it tends to be

diffuse, rather than patchy as in PVOD, but exceptions occur. The

distinction is best appreciated in areas that have the lowest hy-

drostatic pressure, i.e. the ventral-upper areas, where the

patchiness of PVOD/CH stands out more clearly. Pronounced

capillary congestion from any cause, including left heart disease,

may mimic capillary haemangiomatosis.51,52 Veins tend to be

more severely affected than venules in congestive vasculopathy,

whereas small venous and venular intimal fibrosis are more

prominent in PVOD/PCH. Arterialization of veins is a hallmark

feature of congestive vasculopathy, not of PVOD.

When an unequivocal distinction cannot be made, a diagnosismay be reached in multidisciplinary approach, taking wedge

pressure and clinical information into account.

Pattern 6: none of the above

Some PH cases do not fit in the above categories. This may be

due to bias by early disease stage (e.g. explant vs true end-

stage disease in autopsy), unusual variant of a known pattern,

or theoretically, a hitherto unrecognized pattern. Systemic scle-

rosis and so-called vaso-occlusive disease (VOD) may be in either

of these last 2 categories. In addition, various systemic diseases

may affect lung vessels directly (Wegener, Behcet, sarcoidosis),

or as bystanders (endarteritis obliterans during or after inflam-

matory lung disease).Sarcoidosis may be complicated by PH by several (combina-

tions of) ways53: extensive lung fibrosis,54 mediastinal lymph-

adenopathy or significant left ventricular myocardial involvement

compromising pulmonary venous outflow (causing congestive

vasculopathy), venous granulomatous vasculitis,55 and finally,

liver cirrhosis with portal hypertension due to liver sarcoidosis

may (rarely) account for the PH. Sarcoidosis and Gaucher disease

are in group 5 of the clinical classification.

Sickle cell disease (SCD) deserves to be singled out as patients

have a particularly high risk (up to 40%56,57) of developing PH,

with a mortality rate of almost 50%56,57 (reviewed by Kato58).

The HbS gene is distributed across Africa, some parts of Asia,

and in people of African descent in the Caribbean, North Americaand Europe. Lung involvement, aside from pneumonia, mani-

fests either as acute chest syndrome or as chronic lung disease.

Acute chest syndrome or acute vasculopathy is a potentially fatal

sickle crisis with a clinicoradiological definition. Patients present

with fever, wheeze, cough, tachypnoea, chest pain, bone pain,

hypoxaemia and new pulmonary infiltrates on chest imaging.

Precipitating factors promoting sickling include bacterial pneu-

monia and sepsis, bone sickle cell crisis and necrotic marrow

embolism (Figure 9), pulmonary fat embolism, and general

anaesthesia.58,59 Morphologically, arterioles, capillaries and ve-

nules are dilated and engorged with sickled erythrocytes, occa-

sionally with microvascular thrombosis. Secondary alveolar

septal oedema, necrosis, and haemorrhage are commonly noted,

but infarcts are rare.58,59 Pulmonary oedema and even diffuse

alveolar damage may be seen in fatal crises. One should discern

the iatrogenic effects of cardio-pulmonary resuscitation (CPR)

from acute chest syndrome at autopsy, as CPR can cause fat

embolism to the lung, and after death, sickling of previously non-

sickled red blood cells occurs.

Chronic lung disease with dyspnoea may develop indepen-

dent of the acute chest syndrome. Chronic hypoxia, along with

generalized pulmonary fibrosis leads to PH. It is likely that lung

infarction and ongoing endothelial injury contribute to this state.In addition, haemolysis may detrimentally affect the availability

of the vasodilator NO, and increase cellular exposure to oxi-

dants.58 Finally, left heart failure and hepatic cirrhosis with

portal hypertension may be independent contributing factors.

Thus, the pathogenesis of PH in sickle cell disease is multifac-

torial, rather than purely thrombotic.58 SCD is in group 1 of the

clinical classification (Table 1).1

General remarks

Effects of therapy:much of our knowledge of pulmonary vascular

histopathology was gathered in a time when, apart from cardiac

surgery in cases of cardiac malformations or cardiac valve disease,

treatment options were virtually non-existent. Continuous i.v.

administration of prostacyclin (PGI2, epoprostenol) has been

approved for treatment of primary PH (now idiopathic PAH) since

1998.60 At present, oral endothelin receptor antagonists (e.g.

bosentan), phosphodiesterase 5 inhibitors (e.g. sildenafil) usually

constitutes the first line of treatment, prostanoids is reserved for

second line of treatment. Data on the effects of treatment on

vascular remodelling are sparse. The vascular morphology in

explanted lungs of prostacyclin-treated (treatment duration: 17e64

months) and non-treated patients with either idiopathic PH or

Eisenmengers syndrome were compared.61 Treated cases showed

more frequent and extensive perivascular and peribronchiolar

inflammation and alveolar oedema. Treated and non-treated

Figure 9 Necrotic bone marrow embolus in sickle cell disease. Bonemarrow necrosis is a highly characteristic feature of sickle cell disease,

that often precedes acute chest. While sickling may be wide-spread after

death or biopsy in any case of sickle cell disease, the bone marrow

embolus is the clue towards the sickle cell crisis as the cause of death.




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control groups did not differ with respect to medial, intimal and

adventitial thickness, or number of plexiform lesions. The effect of

oral treatment regiments, and of prolonged survival itself, is as yet

unclear for all patterns of vasculopathy.

Take home message

Pulmonary hypertension is not a pathologists diagnosis. How-

ever, histopathological evaluation of pulmonary vasculopathy is

the mainstay of classification of pulmonary hypertension. Such

evaluation, albeit often on explanted lung or tissue obtained at

autopsy, had added value in identifying specific patterns of

vasculopathy that indicate risk of recurrence and may point to-

wards a specific aetiology of underlying disease. It requires

proper sampling and processing of the tissue, adequate stainings

(HE, elastin stain, iron stain), and thorough knowledge of pul-

monary anatomy. In this paper, a set of clues is described that

will allow histological assessment of pulmonary vasculopathy,

avoiding both the all-encompassing term of pulmonary vascul-

opathy consistent with pulmonary hypertension, and the pitfalls

in distinguishing specific patterns of vasculopathy. The clues tothe 6 patterns are summarized inTable 3, and a simple algorithm

is presented inTable 4. A glossary of terms and abbreviations is

provided inTable 6. A

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Acknowledgements

The authors acknowledge Jaap Velthuysen, medical photographer

for his expertise and support in photo-editing.


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A Practical Approach to Vascular Pathology in Pulmonary Hypertension

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