丁彦青教授：特发性间质性肺炎-2014

特发性间质性肺炎Idiopathic

InterstitialPneumonias

(IIP)丁彦青南方医科大学病理学系南方医科大学南方医院病理科一、导言

特发性间质性肺炎（IIP）是弥漫性肺部浸润性损害、临床表现类似的一组疾病总称。

呼吸困难,肺部限制性通气功能障碍

影像学:双肺间质性浸润性病变

病理改变：肺泡间隔损伤为主伴不同程度的炎细胞浸润与纤维组织增生

本病预后不良，存活时间仅3～５年,至今缺乏特效治疗方法。IIP分类经5次修订2002年美国胸科协会／欧洲呼吸协会(ATS/ERS)分类修订意见，为现在采用的IIP分类方案二、IIP分类

1969年Liebow和Carrington首次提出IIP的概念，提出5种经典类型：①寻常型(普通型)间质性肺炎(usual

interstitial

pneumonia,

UIP)②脱屑性间质性肺炎(desquamative

interstitial

pneumonia,

DIP)③闭塞性细支气管炎性间质性肺炎(bronchiolitis

obliterans

withinterstitial

pneumonia,

BOIP)④淋巴样间质性肺炎(lymphoid

interstitial

pneumonia,

LIP)⑤巨细胞间质性肺炎(giant

cell

interstitial

pneumonia,

GIP)LiebowandCariington1969Katzenstein1997MullerandColby1997ATS/ERS2002UIPUIPUIPUIPDIPDIP/RB-ILDDIPDIPRB-ILDBOOPandDADBOOPCOPAIPAIPAIPNSIPNSIPNSIP-cellularpattern-FibrosingpatternLIPLIPUnclassifiableinterstitialpneumoniaTable

1.

revisions

of

idiopathic

interstitial

pneumonias

classification三、ATS/ERS关于IIP分类的说明1.2.3.

IIP是一组独立疾病，各类型特征不同，在病史、体检、影像学和实验检查、病理表现与其它弥漫性间质性肺疾病不同。IIP少见，诊断和治疗缺乏经验。ATS/ERS认为目前IIP的发生率依次为：

特发性肺纤维化(IPF)

非特异性间质性肺炎(NSIP

)

隐匿性机化性肺炎(COP)

急性间质性肺炎(AIP)

呼吸性细支气管炎相关的肺间质性疾病(RB-ILD)

脱屑性间质性肺炎(DIP)

淋巴细胞性间质性肺炎(LIP)4.正确诊断IIP是一个动态调整与修正

的过程；5.

新分类是建立在临床－影像－病理

三结合的基础上；6.如无禁忌证，推荐外科肺活检术。KEYFEATUREIPF/UIPNSIPDIPRBILDAIPCOPLIP*Ageatonset(yr)>6040–6040–5040–50Anyage40–50AnyageM:FratioMalepredominanceEqualMalepredominanceSlightmalepre-dominanceEqualEqualFemalepredominanceProdromeChronic(>12mo)Subacutetochronic(monthstoyears)Subacute(weekstomonths)Subacute(weekstomonths)Abrupt(1–2wk)Subacute(<3mo)Chronic(>12mo)Historyofcigarettesmoking>60%>40%>90%>90%Unknown<50%UnknownChestx-rayfindingsBasal-predominantreticularabnormalitywithvolumelossGround-glassandreticularopacityGround-glassopacityBronchialwallthickening;ground-glassopacityProgressivedif-fuseground-glassdensity/consolidationPatchybilateralconsolidationReticularopacities,nodulesHigh-resolutionCTfindingsPeripheral,subpleural,basal;reticular;honeycombing;tractionbronchiectasis/bronchiolectasis;architecturaldistortion;focalgroundglassPeripheral,subpleural,basal,symmetric;ground-glassattenuation;irregularlines;consolidationLowerzone,peripheralpredominanceinmost;ground-glassattenuation;reticularlinesDiffusepattern;bronchialwallthickening;centrilobularnodules;patchyground-glassopacityDiffuseconsoli-dationandground-glassopacity,oftenwithlobularsparing;tractionbronchiectasislaterSubpleural/peribronchial;patchycon-solidationand/ornodulesDiffusepattern.Centrilobularnodules;ground-glassattenuation;septalandbronchovascularthickening;thin-walledcystsKEY

FEATURES

OF

IDIOPATHIC

INTERSTITIALPNEUMONIASKEYFEATUREIPF/UIPNSIPDIPRBILDAIPCOPLIP*HistologicpatternUsualinterstitialpneumoniaNSIPDIPRBDiffusealveolardamageOrganizingpneumoniaLIPTreatmentPoorresponsetocorticosteroidorcytotoxicagentsCorticosteroidresponsivenessSmokingcessation;corticosteroidresponsivenessSmokingcessation;corticosteroidresponsivenessMechanicalventilation;corticosteroidresponsivenessunknownCorticosteroidresponsivenessCorticosteroidresponsivenessPrognosis50–70%mortalityin5yrUnclear;<10%mortalityin5yr5%mortalityin5yrRaredeaths60%mortalityin<6moCompleterecoveryin2/3;relapseiscommonNotwelldefinedCTdifferentialdiagnosisAsbestosis;connectivetissuedisease;hypersensitivitypneumonitis;sarcoidosisUsualinterstitialpneumonia;DIP;COP;hyper-sensitivitypneumonitisRBILD;hypersensitivitypneumonitis;sarcoidosis;Pneumocystisjiroveci(formerlyP.carinii)pneumoniaDIP;NSIP;hypersensitivitypneumonitisHydrostaticedema;pneumonia;acuteeosinophilicpneumoniaInfection;vasculitis;sarcoidosis;alveolarcarcinoma;lymphoma;eosinophilicpneumonia;NSIPSarcoidosis;lymphangiticcarcinoma;Langerhans’cellgranulomatosisKEY

FEATURES

OF

IDIOPATHIC

INTERSTITIAL

PNEUMONIAS—ContinuedClassic

idiopathic

pulmonary

fibrosis

in

70-year-old

man.

High-resolution

CT

showsbilateral

subpleural

reticulation,

tractionbronchiectasis

(curved

arrow),

andhoneycombing

(straight

arrows).Classic

idiopathic

pulmonary

fibrosisin

70-year-old

man.

Coronalreformatted

image

shows

characteristicpredominance

of

abnormalities

insubpleural

and

basal

regions.四、IIP的病理类型（一）特发性肺纤维化(IPF/UIP)病理组织学特征主要组织学改变

双肺弥漫性实变区，严重受累处形成多房囊性结构，即蜂窝肺;

纤维化区有数量不等的胶原纤维沉积，炎症细胞相对较少;

增生活跃的肌纤维母细胞和纤维母细胞，基质呈粘液样，位于肺间质，突向被覆呼吸上皮的腔面，形成纤维母细胞灶。（一）特发性肺纤维化(IPF/UIP)病理组织学特征确定诊断须排除如下情况：1.其它肺间质性活动型病变：如肉瘤样病，Langerhans’

组织细胞增生症；2.明显的肺间质慢性炎症；3.明确的肉芽肿性病变；4.肺内尘肺性无机物沉积，如石棉小体等5.明显的嗜酸性白细胞浸润。54-year-old

man

with

severe

idiopathic

pulmonary

fibrosis

who

underwent

lung

transplantation.Photomicrograph

of

histopathologic

specimen

(higher-power

view)

of

less

severely

affected

areasshows

patchy

interstitial

fibrosis

and

occasional

fibroblast

foci

(arrows).

(H

and

E,

x50)UIP：Ⅱ型肺泡上皮增生UIP：纤维化型，弥漫性纤维组织增生Histopathological

image

of

pulmonary

fibrosis

representingfibroblastic

proliferationUsual

interstitial

pneumonia

pattern

showing

(a)

patchy

fibrosis

with

intervening

normallung

parenchyma,

(b,

c)

marked

fibrosis

with

collagenous

scarring,

honeycomb

changesand,

fibroblastic

foci.Modern

Pathology

(2004)

17,

973–980（二）非特异性间质性肺炎（NSIP）主要组织学特点肺间质不同程度的炎症和纤维化1.富于细胞型，主要表现为间质的炎症，很少或几乎无纤维

化，其特点为肺泡间隔内淋巴细胞和浆细胞的混合浸润，间质炎症常常伴有肺泡II型上皮的增生。2.

纤维化型，肺间质以致密的胶原纤维为主，伴有轻－中度的间质慢性炎症3.混合型，间质有大量慢性炎细胞浸润和明显的胶原纤维增生。（二）非特异性间质性肺炎（NSIP）确定诊断须排除如下情况：1.

Cellular

pattern

Dense

interstitial

fibrosis:

absent

Organizing

pneumonia

is

not

a

prominent

feature

Lack

of

diffuse

severe

alveolar

septal

inflammation2.

Fibrosing

patternfibroblastic

foci

with

dense

fibrosis

are

inconspicuousor

absent—this

is

especially

important

in

cases

withpatchy

involvement

and

subpleural

or

paraseptaldistribution3.

Both

patterns

Acute

lung

injury

pattern,

especially

hyalinemembranes:

absent

Eosinophils:

inconspicuous

or

absent

Granulomas:

inconspicuous

or

absent

Lack

of

viral

inclusions

and

organisms

on

specialstains

for

organismsfibroblast

focusinterstitial

chronic

inflammation（a)

Trichrome

stain

showing

collagen

within

interstitium

(b,c).

Nonspecific

interstitialpneumonia

pattern

in

lung

biopsies

showing

homogeneous

expansion

of

interstitium

byinflammatory

cells,

myofibroblasts,

and

Type

II

pneumocytes

hyperplasia.Modern

Pathology

(2004)

17,

973–980

PA912297：NSIP－细胞型Ⅱ型细胞增生SP－A

CKNSIP细胞型PA911934：女，47岁，咳嗽伴呼吸困难进行加重3个月。PA911934：NSIP混合型PA911934：NSIP混合型，SP－A示Ⅱ型上皮细胞着色，支气管上皮阴性。男，49岁，咳嗽、咳痰，加重伴呼吸困难半年PA804665：NSIP纤维化型CKSP－A男，72岁，咳嗽、咳痰4个月，偶伴低热。NSIP：纤维化型，间质轻度纤维化，炎症轻微，Ⅱ型肺泡上皮细胞增生明显

NSIP细胞型NSIP混合型

NSIP纤维化型

NSIP是开胸活检、胸腔镜下活检常见的类型，因

为UIP/IPF通常以病史、HRCT检查可确定诊断。

NSIP临床表现、HRCT与COP、LIP、DIP、RBILD相重叠，临床与影像鉴别诊断困难。

NSIP细胞型、纤维化型和混合型三者分类与预后直接相关，细胞型＞混合型＞纤维化型，三者可

相互转化，而其它类型的IIP不会相互转化。

多部位活检中出现只要有一处出现确定的“蜂窝肺”改变，则应诊断的UIP。主要病理变化1.呼吸性细支气管及以下的小气道和肺泡腔内

机化性肺炎改变；2.病变呈斑片状分布，轻度间质慢性炎症；3.病变位于气腔内，肺结构没有破坏。（三）隐匿性机化性肺炎（COP/BOOP）（三）隐匿性机化性肺炎（COP/BOOP）确诊本病须排除如下情况：1.2.3.4.5.6.7.Lack

of

interstitial

fibrosisAbsence

of

granulomasLack

of

neutrophils

or

abscessesAbsence

of

necrosisLack

of

hyaline

membranes

or

prominent

airspace

fibrinLack

of

prominent

infiltration

of

eosinophilsAbsence

of

vasculitisCryptogenic

Organizing

pneumoniaArchives

of

Internal

Medicine.

161

(2):158-164.

2001Cryptogenic

Organizing

pneumoniaArchives

of

Internal

Medicine.

161

(2):158-164.

2001女，48岁，发热、咳嗽、气促10余天入院，抗炎治疗4周无好转，患者拒绝行手术肺活检。PA911282：COPPA911282：COPPA911282：COPPA911282：COP（四）急性间质性肺炎（AIP）或弥漫性肺泡损伤（DAD）主要病理变化1.弥漫性肺泡损伤的机化期改变2.肺泡间隔显著增宽，增宽肺泡隔内纤维母细胞增生，散在淋巴细胞和浆细胞浸润3.肺泡Ⅱ型上皮增生，细支气管上皮可有鳞状化生4.肺泡腔内可见透明膜形成（四）急性间质性肺炎（AIP）或弥漫性肺泡损伤（DAD）

主要组织特征：1.2.3.4.Diffuse

distributionAlveolar

septal

thickening

due

to

organizing

fibrosis,

usually

diffuseAirspace

organization

(may

be

patchy

or

diffuse)Hyaline

membranes

(may

be

focal

or

diffuse)确诊本病须排除如下情况：1.2.3.4.Lack

of

granulomas,

necrosis,

or

abscessesLack

of

infectious

agents

(no

viral

inclusions

and

negative

results

withspecial

stains

for

organisms)Lack

of

prominent

eosinophils

and

neutrophilsNegative

culturesAIP注意事项

AIP早期为急性肺损伤期，广泛肺损伤、透明膜形成，并发DIC。

AIP后期可出现纤维组织增生，肺泡腔内出现轻度纤维组织增生。

AIP总死亡率为75%-100%。

AIP存活病例可出现局灶性或全肺纤维化。

AIP诊断过程中必须排除病毒性肺炎所致的肺损伤。

风湿性疾病、急性恶化性UIP均可出现AIP样损伤，注意查找原发病的证据，如血管炎、肺组织纤维化等。Diffuse

alveolar

damagea)

Widened

alveolar

septa

due

to

interstitial

oedema

and

numerous

hyaline

membranesare

evident

at

low

magnification.

b)

Extracellular

matrix-containing

spindle

cells

arepresent

in

the

interstitial

and

alveolar

structures

associated

with

fragments

of

hyalinePA911020：女，56岁，呼吸困难进行加重10天，治疗后无效死亡。PA911020：AIP合并DICPA911020：AIP透明膜形成PA911020：AIP弥漫性肺损伤PA911020：AIP小血管内透明血栓PA710248

男，21岁，因咳嗽咳痰1月余，进行性呼吸困难20余天入院。

外院CT示双肺弥漫性毛玻璃样变，痰涂片

中见较多PAS阳性物质，诊断为肺泡蛋白沉积症。

入院后病情进行加重，严重低氧血症，需呼吸机维持通气。

肺泡灌洗时行跨支气管肺活检术，并行临床、影像、病理急会诊。治疗后7个月CT（五）呼吸性细支气管炎相关的间质性肺疾病（RB/RB-ILD）

主要组织学特征1.2.3.Bronchiolocentric

alveolar

macrophage

accumulationMild

bronchiolar

fibrosis

and

chronic

inflammationMacrophages

have

dusty

brown

cytoplasm

(may

be

positive

for

iron

stains)确诊本病须排除如下情况：1.2.Lack

of

diffuse

macrophage

accumulationLack

of

interstitial

fibrosis

and/or

honeycomb

fibrosis（五）呼吸性细支气管炎相关的间质性肺疾病（RB/RB-ILD）主要病理变化1.病变局限在呼吸性细支气管，可见大量含色素的巨噬细胞聚集2.有明显的呼吸性细支气管炎，肺泡间隔增厚和上皮化生等Respiratory

bronchiolitis/interstitial

lung

disease

with

fibrosis.

At

scanningmagnification,

bronchioles

and

peribronchiolar

airspaces

contain

smokersmacrophages

while

centrilobular

and

subpleural

architecture

and

structure

ispreserved

although

alveolar

septa

are

irregularly

thickened.Modern

Pathology

(2006)

19,

1474–1479Respiratory

bronchiolitis:

interstitial

lung

disease

with

fibrosis.

There

isobvious

irregular

alveolar

septal

thickening

in

the

setting

of

respiratorybronchiolitis

and

mild

emphysematous

change.Modern

Pathology

(2006)

19,

1474–1479Respiratory

bronchiolitis/interstitial

lungdisease

with

fibrosis.

More

extensiveseptal

disease

was

characterized

bydiffuse

septal

fibrosis

with

retainedparenchymal

structure.

Patchy

airspacefilling

by

smokers

macrophages

is

seen.The

thickened

septa

were

composedof

amyloid-like

lamellae

of

denseropey

eosinophilic

collagen,

with

mildprominence

of

alveolar

lining

cells

butno

bronchiolar

metaplasia

orhoneycomb

change.Modern

Pathology

(2006)

19,

1474–1479可疑病例：RBILD

女性，37岁，干咳3个月入院。

患者3个月前无明显诱因出现干咳，无痰，活动后及咳嗽剧烈时感轻微胸闷，平卧时为甚。

2个月前在外院胸片示“肺间质纤维化”，肺功能示“弥散障碍”。

查体所见：双肺呼吸音清，右肺呼吸音稍弱，未闻及干湿罗音。

初步诊断：弥漫性肺疾病：间质性肺炎？肺泡蛋白沉积症？

行跨支气管肺活检术。（六）脱屑性间质性肺炎（DIP）

The

term

DIP

is

retained

in

this

document

but

it

presents

severalproblems.

The

name

originated

from

the

belief

that

the

dominanthistologic

feature

was

desquamation

of

epithelial

cells.

However,

this

isnow

recognized

to

be

intra-alveolar

macrophage

accumulation

ratherthan

desquamation

of

epithelial

cells.

Second,

the

condition

is

considered

by

many

to

represent

the

end

of

aspectrum

of

RB-ILD

in

view

of

its

similar

pathology

and

almostinvariable

association

with

cigarette

smoke,

rare

cases

occur

innonsmokers.

The

panel

seriously

considered

changing

this

term

to

alveolarmacrophage

pneumonia,

which

is

a

more

accurately

descriptive

term.（六）脱屑性间质性肺炎DIP主要病理变化

弥慢性的肺泡内巨噬细胞聚集;

除了肺泡壁轻至中度增厚外，无纤维化瘢痕、蜂窝肺，纤维母细胞灶缺如或不明显;

间质有少量淋巴细胞和浆细胞浸润。主要组织学特征1.Uniform

involvement

of

lung

parenchyma2.Prominent

accumulation

of

alveolar

macrophages

(may

show

fine

granularpositivity

with

iron

stains)3.Mild

to

moderate

fibrotic

thickening

of

alveolar

septa4.Mild

interstitial

chronic

inflammation

(lymphoid

aggregates)确诊本病须排除如下情况：1.Dense

and

extensive

fibrosis:

inconspicuous

or

absent

2.Smooth

muscle

proliferation:

inconspicuous

or

absent

3.Honeycomb

fibrosis

absent4.Fibroblastic

foci

and

organizing

pneumonia:

inconspicuous

or

absent5.Eosinophils:

inconspicuous,

absent,

or

only

focal63-year-old

man

with

biopsy-proven

desquamative

interstitial

pneumonia(DIP).

High-resolution

CT

(HRCT)

shows

patchy

bilateral

areas

of

ground-glass

opacity

and

mild

reticulation.63-year-old

man

with

biopsy-proven

desquamative

interstitial

pneumonia

(DIP).Photomicrograph

of

histopathologic

specimen

obtained

by

surgical

biopsy

shows

mildthickening

of

alveolar

septa

and

extensive

airspace

filling

by

macrophages

(arrows).

(Hand

E,

x100)

Inset:

Higher-power

view

shows

airspace

macrophages

and

chronicinterstitial

inflammatory

infiltrate

(arrow).

(H

and

E,

x250)

Findings

are

characteristic

of

DIP.脱屑性间质性肺炎

男，32岁，发热，咳嗽，胸闷2个月，加重10余天。体温达39度以上，以夜间为著。

既往健康，半年前因痛风服用秋水仙碱近3个月；

白细胞下降WBC3.0×109/L；

骨穿：粒系明显活跃增生；红细增生、活跃。

外周血：淋巴细胞比值增高；

纤支镜检查：涂片（-）

TB菌（-）；

肺穿刺组织涂片查：TB（-）真菌：（-）；

抗核抗体：ANA

1：160；

血常规：WBC

4×109/L；

血沉：10mm/h。会诊病例：DIP治疗后CT

（七）淋巴细胞性间质性肺炎(LIP)主要组织学特征：1.2.3.4.Diffuse

interstitial

infiltration

of

involved

areasPredominantly

alveolar

septal

distributionInfiltrates

comprise

mostly

T

lymphocytes,

plasma

cells,

and

macrophagesLymphoid

hyperplasia

(MALT

hyperplasia)—frequent确诊本病须排除如下情况：1.2.3.4.5.Organizing

pneumonia,

inconspicuous

or

absen