경희대학교 의과대학·의학전문대학원

(1)

광범위 사이질 폐질환

• 폐포벽의 결합조직에 주된 변화를 초래하는 질환으로 보통 만성으로 진행되며 진행되며, • 방사선소견에서 폐의 양엽을 광범위하게 침범 (“infiltrative”)하고 – Small nodules – Irregular linesIrregular lines

– Ground-glass shadows • 제한성 (restrictive) 폐기능검사의 소견을 특징으로 한다. • 원인과 발병기전이 분명치 않으나 여러 가지 원인에 의하여 손상받은 폐에서 폐포염이 발생한 후 섬유화로 진행되는 공통성을 가지고 있다. • 초기에는 원인 질환이 어느정도 구별이 가능하나 진행이 되면 반흔조 직 형성과 파괴를 가져오는 결과로 소위 “말기폐 (end-stage lung)” 혹은 “벌집폐 (h b l )”로 되어 서로 구별하기 힘들게 된다 혹은 “벌집폐 (honeycomb lung)”로 되어 서로 구별하기 힘들게 된다. • 호흡곤란을 주소로 내원하게 되나, 결국 허혈증으로 인한 청색증이 생 기고 호흡기능상실로 진전된다 기고 호흡기능상실로 진전된다.

(2)

Microscopic Approach to Lung Biopsy Interpretation

E i ti t l ifi ti

• Examination at low magnification

– Determine predominant site of involvement

• Airspace • Interstitial • Interstitial

• Mixed airspace-interstitial

– Assess extent – patchy or diffuse?

• If patchy, determine distribution pattern:p y, p

– Random

– Specific (bronchiolar, lymphangitic, arterial)

E i ti t hi h ifi ti

• Examination at high magnification

– Evaluate nature of process

• Cellular

– Reactive (inflammatory / infectious)Reactive (inflammatory / infectious) – Neoplastic

– Necrotizing /non-necrotizing – Metabolic

(3)

Major Categories of Chronic Interstitial Lung Disease

• Fibrosing Diseases

– Usual interstitial pneumonia (Idiopathic pulmonary fibrosis) (UIP, IPF) – Nonspecific interstitial pneumonia (NSIP)p p ( )

– Cryptogenic organizing pneumonia (COP, BOOP) – Associated with collagen vascular disease

– Pneumoconiosis (진폐증) Drug reactions

– Drug reactions

– Radiation pneumonitis

• Granulomatous DiseasesGranulomatous Diseases

– Sarcoidosis

– Hypersensitivity pneumonitis (HP)

P l i hili

• Pulmonary eosinophilia

• Smoking-Related Interstitial Diseases

Desquamative interstitial pneumonia (DIP) – Desquamative interstitial pneumonia (DIP)

– Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

• Others

(4)

Usual Interstitial Pneumonia (UIP, IPF)

보통형 사이질폐렴

= “Idiopathic Pulmonary Fibrosis” (IPF)

= “Cryptogenic fibrosing alveolitis” in Europe

• 원인불명의 만성 간질성 폐렴을 가진 환자에서

볼 수 있는 가장 흔한 형태

• 40, 50대의 호흡곤란과 비객담성 기침을 주소로

insidiously, gradually 진행함

(5)

Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)

(6)

Usual Interstitial Pneumonia (UIP, IPF)

보통형 사이질폐렴

• Morphology

Gross

• Pleural surface = cobblestone appearance (owing to retraction of scar along the interlobular septa)

• Cut surface

– Fibrosis (firm, rubbery white areas)

• Lower lobe predominance

• Distinctive distribution in the subpleural regions and along the interlobular septa

(7)

Usual Interstitial Pneumonia (UIP, IPF)

보통형 사이질폐렴

Traction

bronchiectasis

• (A) This CT scan shows the early subtle findings in UIP, with delicate pleural-based reticular opacities in the lower lung delicate pleural based reticular opacities in the lower lung

(8)

(9)

( )

• The gross lung specimen in UIP shows subpleural (P) cysts ranging from a few millimeters in diameter to a centimeter or more (radiologic “honeycombing”), that increase in prominence as the disease advances.

(10)

Usual Interstitial Pneumonia (UIP, IPF)

보통형 사이질폐렴

• Morphology ★

Mi – Microscope 1) 저배율에서 폐손상이 일어난 병변이 이질적 (heterogeneous) 소 견을 보인다. 정상의 폐조직 간질의 염증 섬유화 h b 변화가 현미경 시야 – 정상의 폐조직, 간질의 염증, 섬유화, honeycomb 변화가 현미경 시야 를 달리하면서 번갈아 나타나는 것이 특징이다. (variable intensity with time) 2) 간질의 염증 또는 섬유화는 보통 반점상으로 나타난다. (patchy) 간질의 염증 는 섬유화는 통 반점상 나타난다. (patchy interstitial fibrosis)

3) Fibroblastic foci) Æ more collagenous and less cellularg (coexistence of both early and late lesions)

4) Dense fibrosis Æ collapse alveolar wall Æ honeycomb fibrosis (세기관지 상피세포로 피복되고 점액이 차있다)

5) 폐포 중격 내에 림프구, 형질세포, 조직구의 침윤을 보이고 II형의 pneumocyte의 증식을 동반한다.

6) Squamous metaplasia, 평활근 증식도 섬유화 및 벌집모양을 보이 는 부위에서 흔히 관찰된다.

(11)

• (A) The remodeled lung is present mainly beneath the pleura and at the periphery of the beneath the pleura and at the periphery of the secondary lobule, adjacent to interlobular septa. A slightly shrunken lobule is circled at upper center (CL = center of lobule).

• (B) An interlobular septum (ILS) widened by(B) An interlobular septum (ILS) widened by fibrosis, with less involved lung lobules above and below center.

• Microscopic honeycomb cysts are considerably p y y y smaller (in the range of 1–3 mm) than those identified radiologically.

(12)

• Microscopic honeycomb cysts are lined by • Microscopic honeycomb cysts are lined by

columnar ciliated epithelium and typically are filled with mucus, with variable amounts of acute inflammation and inflammatory debris. When dense chronic inflammation is present around microscopic honeycombing

around microscopic honeycombing. • The subpleural fibrous tissue contains

(13)

• This transition occurs through

t h f lu i ju

patchy areas of lung injury evidenced by the “fibroblast” or “fibroblastic” focus (ff)

• Fibroblastic focus with fibers running parallel to surface and bluish myxoid extracellular

bluish myxoid extracellular matrix.

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 10 April 2006 08:59 AM)

(14)

Diagnostic histologic features of UIP

• Non-uniform interstitial fibrosis

with patchwork pattern

Æ spatial variegation

• Interstitial scars

Honeycomb change

Æ Architectural

di

i

Honeycomb change

• Active ongoing fibrosis +

(fib bl

ti f

i)

distortion

Æ Temporal

(fibroblastic foci)

Inactive collagen-type fibrosis

Æ Temporal

variegation

• Inflammation overshadowed by

fibrosis

Æ Mild inflammation

(15)

Clinical Course of UIP

• Begin insidiously, gradually increasing dyspnea on exertion and dry cough

• 40-70 years old at the time of presentation

• Gradual deterioration of pulmonary status, despite medical treatment (steroids, cyclophosphamide, azathioprine)

• In some patients, Acute exacerbation (diffuse alveolar damage) with rapid downhill clinical course

• Mean survival: 3 years or less

• Lung plantation is the only definitive therapy • Lung plantation is the only definitive therapy.

(16)

Non-Specific Interstitial Pneumonia (NSIP)

비특이 사이질폐렴

Diffuse interstitial lung disease of unknown etiology • Diffuse interstitial lung disease of unknown etiology

(“wastebasket”?)

• Distinct radiologic and histologic features

Hi t l i tt : C ll l tt d Fib i tt – Histologic patterns: Cellular pattern and Fibrosing pattern

• 46-55 years of age

• Celluar pattern are somewhat younger those with the fibrosing pattern or UIP

• Cellular patterns have a better outcome than do those with fibrosing pattern

(17)

Nonspecific insterstitial pneumonia (NSIP)

• Morphology • Morphology

– Cellular and fibrosing patterns

• Cellular pattern

– Mild to moderate chronic interstitial inflammation, containing lymphocytes , g y p y and a few plasma cells

– Uniform or patchy distribution

• Fibrosing pattern

– Diffuse or patchy, interstitial fibrosis without the temporal heterogeneity

– Fibroblastic foci are absent

• Three major subgroups

– Group I

• Primarily with interstitial inflammationy

– Group II

• Both inflammation and fibrosis

– Group IIIp

(18)

(19)

• The chronic inflammatory infiltration in NSIP is diffuse

and relatively uniform, mainly involving the alveolar

walls (cellular NSIP)

walls (cellular NSIP).

(20)

• When fibrosis occurs in NSIP (so-called “fibrotic NSIP”), it is usually mild to moderate in amount and preserves lung structure usually mild to moderate in amount and preserves lung structure, generally without microscopic honeycombing, or heterogeneity.

(21)

Separation of Fibrosing NSIP from UIP

Features NSIP, Fibrosing Pattern, g UIP Clinical

Age (range) _{49 years (11-78)} _{51 years (27-70)} Sex (M:F) _28:27 _73:37

Sex (M:F) _28:27 _73:37 Duration of Symptoms _{8 mos. (1wk-5yrs)} _{2.5 years}

Radiology

M i fi di _G _d _l _tt _ti _I _l _li _h _bi Main findings _{Ground-glass attenuation} _{Irregular lines, honeycombing} Predominant distribution _{Diffuse or patchy} _{Middle and lower lung zones,}

subpleural in >90% of cases Pathology

Pathology

Temporal appearance _Uniform _{Heterogeneous} Interstitial inflammation _{Mild to marked} _Mild

D i i i l fib i

Dense interstitial fibrosis _{Variable, diffuse or patchy} _Patchy Organizing pneumonia _{Not uncommon} _Uncommon

Fibroblastic foci _{Absent or inconspicuous} _{Characteristic feature} Honeycomb fibrosis _{Rare, inconspicuous} _Frequent

Alveolar macrophages _{Occasional, patchy} _{Occasional, focal}

Prognosis

5-year survival _90% _20-45% 10-year survivial _35% _10-15%

(22)

Bronchiolitis Obliterans Organizing Pneumonia (BOOP)

폐쇄세기관지-기질화 폐렴 (붑)

폐쇄세기관지 기질화 폐렴 (붑)

= Cryptogenic Organizing Pneumonia (COP) = Cryptogenic Organizing Pneumonia (COP) • Dyspnea and cough

• Radiologically,

– Subpleural or peribronchial patchy areas of airspace consolidationp p p y p

• Histologically,

– Polypoid plugs of loose organizing connective tissue (Masson body) within alveolar ducts, alveoli and bronchioles

within alveolar ducts, alveoli and bronchioles. – Underlying architecture is normal

• 저절로 좋아지기도 하나 대부분은 steroid 치료에 의해 좋아진다 • 저절로 좋아지기도 하나, 대부분은 steroid 치료에 의해 좋아진다. • Response to infection or inflammatory process

(23)

Etiologic consideration in BOOP

g

• Idiopathic disease (Idiopathic BOOP or COP)

• Response to infection and inflammatory process

– Prior infection

• viral, bacterial, postobstructive

Toxic inhalants – Toxic inhalants

• nitrogen dioxide, in silo-filler’s lung, aerosol from spray printing, coccain, etc

– Drug reactions

• gold, amiodarone, sufasalazine, minocycline, nitrofurantoin, bleomycin, etc

Radiation of the breast – Radiation of the breast – Collagen vascular disease

• RA, Lupus, polymyositis, etc

– GVHD (graft-versus-host disease) in BMT (bone marrow transplantation) A i i

– Aspiration

• Nonspecific reaction change

Edge of granulomas infarcts neoplasm vasculitis abscess etc – Edge of granulomas, infarcts, neoplasm, vasculitis, abscess, etc

• Minor component of other respiratory illness

– Hypersensitivity pn., NSIP, eosinophilic pn., Langerhans cell histiocytosis,Hypersensitivity pn., NSIP, eosinophilic pn., Langerhans cell histiocytosis, etc

(24)

BO / BOOP (COP)

Fibroblastic Plug

T. bronchiole

Fibroblastic Plug

Alveolous

Bronchus

BO (bronchiolitis obliterans) + OP (organizing pneumonia)

Alveolar duct

(25)

Cryptogenic organizing pneumonia (COP, BOOP)

폐쇄세기관지 기질화 폐렴 (붑)

폐쇄세기관지-기질화 폐렴 (붑)

• Subpleural, peribronchial patchy

consolidation, lower lobe

“Masson bodies”

• Polypoid plugs (“fibroblastic plug”) of loose

Masson bodies

organizing connective tissue within alveolar

ducts, alveoli and often bronchioles

– Connective tissue : all of the same age

– Underlying lung architecture is normal

(26)

Cryptogenic Organizing Pneumonia (COP)

Cryptogenic Organizing Pneumonia (COP),

특발성 기질화폐렴, BOOP

Alveolar spaces are filled with balls of fibroblasts (Masson bodies) Alveolar spaces are filled with balls of fibroblasts (Masson bodies),

while the alveolar walls are relatively normal.

(27)

(28)

S ll d “BOOP ” A l f i dl • So-called “BOOP.” A plug of spindle

mesenchymal cells obstructs a terminal bronchiole.

• There is fibrin deposition and chronic

i fl ti i th di

inflammation in the surrounding parenchyma.

(29)

Pulmonary Involvement in Collagen Vascular Disorders

1. Progressive systemic sclerosis (scleroderma)

• Diffuse interstitial fibrosis (NSIP, more common than UIP)

2. Systemic lupus erythematosus

• Transient parenchymal infiltrates • Transient parenchymal infiltrates

• Severe lupus pneumonitis (occasionally)

3 Rh

t id

th iti 시

l

i

l

t :

3. Rheumatoid arthritis시 pulmonary involvement :

4가지 형태 ★ • RA 환자의 30~40%에서 abnormal pulmonary function 을 보

인다 ( )

(1) Chronic pleuritis with or without effusion (2) Diffuse interstitial pneumonitis and fibrosis (3) Intrapulmonary rheumatoid nodules

(4) Pulmonary hypertension

4 Poor prognosis but better than UIP

4. Poor prognosis, but better than UIP

(30)

• Late stage of interstitial pneumonitis in a patient with

Late stage of interstitial pneumonitis in a patient with

lupus erythematosus.

(31)

(32)

Major Categories of Chronic Interstitial Lung Disease

– Usual interstitial pneumonia (Idiopathic pulmonary fibrosis) (UIP, IPF) N ifi i t titi l i (NSIP)

– Nonspecific interstitial pneumonia (NSIP)

– Pneumoconiosis D ti – Drug reactions – Radiation pneumonitis • Granulomatous Diseases – Sarcoidosis – Hypersensitivity pneumonitis (HP) • Pulmonary eosinophilia

– Desquamative interstitial pneumonia (DIP)

– Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)Respiratory bronchiolitis associated interstitial lung disease (RB ILD)

• Others

(33)

Sarcoidosis

• Systemic disease of unknown cause

y

• Non-caseating granuloma (hard granuloma) in many

tissue and organs ★

– Mycobacterial or fungal infection & berylliosis도 hard granuloma를 만들기 때문에 조직 학적 진단은 exclusive diagnosis해야 함

diagnosis해야 함

• Bilateral hilar lymphadenopathy 또는 lung

i

l

t 90%에서 h

t

상 관찰됨

involvement : 90%에서 chest x-ray상 관찰됨

• Eye skin lesion : next in frequency (25%)

Eye. skin lesion : next in frequency (25%)

• Female > male

(34)

Sarcoidosis

1. Etiology and pathogenesis

gy

p

g

(1) Immunological factors

• Cell-mediated response to an unidentified antigen (driven by CD4+ Cell mediated response to an unidentified antigen (driven by C 4 helper T-cell)

• Lung내의 CD4+ T cell증가 (CD4:CD8=5:1-15:1)

• IL-2 and IFN-γ 증가 Æ T-cell expansion and macrophage activation • IL 2 and IFN γ 증가 Æ T cell expansion and macrophage activation • IL-8, TNF, macrophage inflammatory protein 1α 증가 Æ influx of T-cells

and monocytes Æ noncaseating granuloma formation

(TNF concentration in bronchoalveolar (BAL) fluid is a marker of disease activity)

(2) Genetic factors

• Familial and racial clustering of cases

• Association with HLA genotypes (HLA-A1 and HLA-B8)Association with HLA genotypes (HLA A1 and HLA B8)

(3) Environmental factors

(35)

Sarcoidosis

2. 형태 ★

(1) Micro :

–

Non-caseating granuloma가 특징

Non caseating granuloma가 특징

–

Central necrosis는 unusual

(2) Two other microscopic features

: not pathognomonic feature (다른 granulomatous

not pathognomonic feature (다른 granulomatous

lesion에도 보임: berylliosis)

1) Schaumann body

l i d i d f l i &

– laminated concretions composed of calcium & protein

2) Asteroid body (stellate inclusion) in giant cell » 60% of the granuloma

(36)

Ch t i ti id ti l i l ith i t ll Characteristic sarcoid noncaseating granulomas in lung with many giant cells.

(37)

Schaumann body

(38)

Sarcoidosis

2. 형태 ★

(3) Lung: common site of involvement

1) 육안적으로는 보통 특별한 변화가 없으나, 때로 1~2㎝ 크기 의 small nodule (coalescence of granuloma)이 보임

2) non caseating non cavitated consolidations 2) non-caseating, non-cavitated consolidations

3) 조직학적으로 bronchi와 혈관주위의 lymphatic를 따라 분포) y p 4) Granuloma가 상대적으로 bronchial submucosa에 많이 분

포 비교적 진단적 가치가 높은 소견임 포 : 비교적 진단적 가치가 높은 소견임

5) Varying stages of fibrosis and hyalinization( → interstitial 5) Varying stages of fibrosis and hyalinization( interstitial

(39)

Sarcoidosis

(40)

Sarcoidosis

(41)

Sarcoidosis

2 형태 2. 형태

(4) Lymph node

• involved in almost all cases, 특히 hilar and mediastinal lymph nodes, enlarged discrete calcified

enlarged, discrete, calcified, • tonsil - 1/4~1/3에서 involve (5) Spleen (5) Spleen • 3/4에서 침범되지만 커지는 경우는 1/5정도 • capsule은 involve 안됨 (6) Liver

• moderately enlarged, scattered granuloma, portal triad에 더 잘 생김

(7) Bone marrow

• systemic involvement있는 경우의 1/5에서 관찰됨 • phalangeal bone of hand and feet에 호발p g 에 발

(42)

Sarcoidosis

2. 형태

(8) Skin

1/3 1/2 육안소견이 다양함 • 1/3~1/2, 육안소견이 다양함

– discrete subcutaneous nodule

– focal, slightly elevated, erythematous plaque – flat lesion

(9) Eye

• 1/5~1/2 : iritis (홍채염), iridocyclitis (홍채모양체염) → corneal

i l (녹내장) l l f i i

opacity, glaucoma (녹내장), total loss of vision

(10) Parotid, submaxillary, subligual gland의 bilateral involvement :

involvement :

• Mikulicz syndrome:

– combined uveoparotid involvement

– salivary and lacrimal gland inflammatory enlargement with xerostomia (구강건y g y g 조증)

(11) Muscle involvement

S id iti

(43)

Sarcoidosis

• Stage

0: 흉부방사선소견상 정상 1: 20-40%, 양쪽 폐문 림프절 증대 2: 20-50%, 양쪽폐문 림프절 증대 + 폐침범 3: 5-15% 폐침범만 있는 경우 3: 5 15%, 폐침범만 있는 경우

• 예후

– 자연치유 되거나 경미한 증상 (65-70%) – 폐기능장애와 시력장애를 초래하는 경우 (20%)폐기능장애와 시력장애를 초래하는 경우 (20%) – 진행폐섬유화에 의해 폐성심(cor pulmonale)을 일으키는 경우 (10-15%)

(44)

Hypersensitivity Pneumonitis

과민성 폐장염

Spectrum of immunologically mediated predominantly interstitial • Spectrum of immunologically mediated, predominantly interstitial

lung disorders caused by intense & often prolonged exposure to inhaled organic dusts and occupational antigens

• Abnormal sensitivity or heightened reactivity to antigen, but asthma와 달리 주로 alveoli에 involve (“Allergic Alveolitis”) • Antigens

• Thermophilic bacteria, true fungi, animal proteins, or bacterial products

products

Farmer's lung (농부폐)

Pigeon breeder's lung (bird fancier‘s disease) (비둘기 사육사 폐) Humidifier or air-conditioner lung (습도조절기 폐)

Mushroom picker's lung (버섯줍는이 폐)

• Antigen의 초기 발견과 제거가 중요 → 심한 chronic fibrotic lung disease로 진행 막음

(45)

Hypersensitivity Pneumonitis

과민성 폐장염

1. 발병기전

(1) Early : type III (immune complex)

hypersensitivity

(2) Later : T-cell mediated (type IV)

delayed-hypersensitivity reactions for

(46)

Hypersensitivity Pneumonitis

과민성 폐장염

2 형태 :

b

hi l

i di

ib i

2. 형태 :

bronchiolocentric distribution

(1) I t

titi l

iti (l

h

t

l

ll

(1) Interstitial pneumonitis (lymphocyte, plasma cell

& macrophage)

(2) Noncaseating granulomas (2/3 of patients)

(3) Interstitial fibrosis, honeycombing

(4) Obliterative bronchiolitis (late stage)

(5) 반 이상에서 intra-alveolar infiltrate

(47)

Hypersensitivity Pneumonitis

과민성 폐장염

Hypersensitivity pneumonitis histologic Hypersensitivity pneumonitis, histologic

appearance. Loosely formed interstitial granulomas and chronic inflammation are characteristic.

HSP produces a chronic inflammatory interstitial pneumonia associated with bronchiolitis and small, indistinct,

(48)

Hypersensitivity Pneumonitis

과민성 폐장염

(A) Bronchiolitis is expected in HSP, manifested here as aggregates of lymphocytes and plasma cells surrounding a terminal airway.

(B)Presumably, as a consequence of bronchiolitis and some degree of ( )P esumably, as a consequence of b onchiolitis and some deg ee of

obstruction, prominently vacuolated macrophages may be present in a bronchiolocentric distribution.

(49)

Hypersensitivity Pneumonitis

과민성 폐장염

A) In chronic hypersensitivity pneumonitis, prominent bronchiolization (Lambertosis) attests to chronic airway injury from inhaled antigen.

B) D fib i ith i i h bi bli l i t titi l

B) Dense fibrosis with microscopic honeycombing resembling usual interstitial pneumonia (UIP) may also be seen.

(50)

Hypersensitivity Pneumonitis

과민성 폐장염

3. 임상경과

(1) Sensitized patient가 antigenic dust를 inhalation

→ acute attack

1) Recurring attacks of fever, dyspnea, cough, leukocytosis: 노출되고 4~6시간 후

노출되고 4~6시간 후

2) Chest X-ray: diffuse and nodular infiltrates

3) Pulmonary function test: acute restrictive effect

(2) Continuous and protracted exposure → chronic

form

1) progressive respiratory failure, dyspnea, cyanosis

2) ↓T t l lu ity d li

(51)

Pulmonary Eosinophilia

= Pulmonary Infiltration with Eosinophilia

↑ l l l l f i hil (IL )

• ↑alveolar levels of eosinophil attractants (IL-5)

Pulmonary Eosinophilia

(Pulmonary Infiltration with Eosinophilia)

1. Acute eosinophilic pneumonia with respiratory failure 1. Acute eosinophilic pneumonia with respiratory failure

– Unknown cause

– Rapid onset with fever dyspnea hypoxic respiratory failureRapid onset with fever, dyspnea, hypoxic respiratory failure – Chest x-ray: diffuse infiltrates

– Prompt response to corticosteroids

2. Löeffler syndrome

– Transient pulmonary lesion

– Blood내의 eosinophilia

– Benign clinical course

– 형태

1) Thickened alveolor septae by eosinophils and giant cell 2) Alveolar epithelial lining cell의 focal hyperplasia

2) Alveolar epithelial lining cell의 focal hyperplasia 3) But, no vasculitis, fibrosis, necrosis

(53)

Pulmonary Eosinophilia

(Pulmonary Infiltration with Eosinophilia)

3 Ch

i

hili

i

3. Chronic eosinophilic pneumonia

특징

– 특징

1) Focal areas of cellular consolidation

2) 병변은 주로 lung fields의 periphery에 생김 2) 병변은 주로 lung fields의 periphery에 생김

– 형태학적 소견

• Alveolar space와 septal wall에 lymphocyte와 eosinophils 의 heavy aggregation

– High fever, night sweat, dyspnea

(54)

Acute Eosinophilic Pneumonia

I t i hili i th

In acute eosinophilic pneumonia, the alveolar spaces are diffusely filled with eosinophils and plump

eosinophilic macrophages

Fibrinous airspace exudates are commonly present, typically with admixed eosinophils, as seen here. eosinophilic macrophages

(55)

Major Categories of Chronic Interstitial Lung Disease

– Usual interstitial pneumonia (Idiopathic pulmonary fibrosis) (UIP, IPF) N ifi i t titi l i (NSIP)

– Nonspecific interstitial pneumonia (NSIP)

– Pneumoconiosis D ti – Drug reactions – Radiation pneumonitis • Granulomatous Diseases – Sarcoidosis – Hypersensitivity pneumonitis (HP) • Pulmonary eosinophilia

– Desquamative interstitial pneumonia (DIP)

– Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)Respiratory bronchiolitis associated interstitial lung disease (RB ILD)

• Others

(56)

Smoking related disease

Smoking-related disease

• Obstructive disease

– Emphysema

– Chronic bronchitis

• Restrictive or interstitial disease

Restrictive or interstitial disease

– Desquamative interstitial pneumonia (DIP)

– Repiratory bronchiolitis-associated

(57)

Desquamative Interstitial Pneumonia (DIP)

탈락사이질폐렴

• Large collection of airspace macrophages

• Misnomer “desquamative”

_{Å originally}

thought to be desquamated pneumocytes

• 30-40대, more common in men (2:1)

• 다른 ILD보다 steroid에 대한 반응이 좋고 예후

도 좋다

도 좋다.

(nearly 100% response to steroid therapy and cessation of smoking)

(58)

Desquamative Interstitial Pneumonia (DIP)

탈락사이질폐렴

• 형태

– Air space안에 large number of macrophages

Air space안에 large number of macrophages

• containing dusty brown pigment (“smokers’ macrophages”) • Finely granular iron

• Lamellar bodies (surfactant) within the phagocytic vacuoles p g y (derived from necrotic type II pneumocyte)

– Interstitial pneumonitis (sparse infiltrate of

Interstitial pneumonitis (sparse infiltrate of

lymphocytes, plasma cells, eosinophils)

Mild i

i i l fib

i

– Mild interstitial fibrosis

(59)

Desquamative Interstitial Pneumonia (DIP)

탈락사이질폐렴

• DIP is often a scanning magnification diagnosis

• The surgical lung biopsy has an eosinophilic appearance due to the presence of eosinophilic

magnification diagnosis. _{the presence of eosinophilic}

macrophages uniformly filling airspaces.

(60)

Desquamative Interstitial Pneumonia (DIP)

The accumulation of large numbers of mononuclear cells within the alveolar spaces with only mild fibrous thickening of the alveolar walls.

(61)

Respiratory Bronchiolitis-associated

Interstitial Lung Disease (RB-ILD)

• RB (respiratory bronchiolitis) :

– A common histologic lesion found in cigarette smokers – Characterized by the presence of pigmented intraluminalCharacterized by the presence of pigmented intraluminal

macrophages within 1st- and 2nd-order respiratory bronchioles

– Incidental findings in the lungs of smokers and ex-smokersg g

• RB-ILD :

Develop significant pulmonary symptoms abnormal – Develop significant pulmonary symptoms, abnormal

pulmonary function, and imaging abnormalities

S t

– Symptoms

• Usually mild, gradual onset of dyspnea and cough, 30-40대 • Average exposure of over 30 pack-years of cigarette smoking

2:1 l d i

• 2:1 male predominance

(62)

Respiratory Bronchiolitis-associated

Interstitial Lung Disease (RB-ILD)

• Morphology

– Patchy and bronchiolocentric distributiony

– Dusty brown macrophages (smokers’ macrophages) in respiratory bronchiole, alveolar duct, and peribronchiolar space

– Patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes

– Mild peribronchiolar fibrosis, extends contiguous alveolar septa

– Centrilobular emphysema is common but not severeCentrilobular emphysema is common but not severe

– Histologic overlap with DIP is often found in different parts of the same lung

(63)

Iron stain

Dusty brown macrophages (smokers’ macrophages)p g

• Metaplastic bronchiolar epithelium extends out from terminal airways to involve alveolar ducts

(64)

• RB is characterized by the presence of scant inflammation y p around the terminal airways (bronchiolocentric).

(65)

Scant peribronchiolar fibrosis may be present and this may • Scant peribronchiolar fibrosis may be present and this may

(66)

Pulmonary Alveolar Proteinosis (PAP)

폐포단백증

• Rare disease

• X-ray상 bilateral patchy pulmonary opacification이 특징이며 • X ray상 bilateral patchy pulmonary opacification이 특징이며

• 조직학적으로 intra-alveolar and bronchiolar space 내에 acellular surfactant의 accumulation (abundant lipid와 PAS positive material)

• Three classes (different pathogenesis, but similar histologic changes)

– Acquired : 90 % – Congenital : rare

– Secondary : uncommonSecondary : uncommon

• Adult

– Most : benign course

• nonspecific respiratory difficulty of insidious onset cough and abundant sputum (gelatinous material) • nonspecific respiratory difficulty of insidious onset, cough, and abundant sputum (gelatinous material)

– Long lasting

• Risk for secondary infection

– Whole-lung lavage : current standard of care – GM-CSF therapy : effective in 50% of patientspy p

• Congenital

– Fatal, usually immediately apparent in newborn

With t l t l t ti Æ d th (3 6 th f ) – Without lung transplantation Æ death (3~6 months of age)

(67)

Pulmonary Alveolar Proteinosis (PAP)

폐포단백증

• Acquired PAP

– 90% of all cases of PAP

– Lack of familial predisposition Autoimmune disorder

– Autoimmune disorder

• Anti-GM-CSF antibody inhibit Inhibits activity of endogenous GM-CSF (granulocyte-macrophage colony-stimulating factor)

• Æ functional GM CSF deficiency • Æ functional GM-CSF deficiency

• Recurrence of PAP following bilateral lung transplantation

S d PAP

• Secondary PAP

– Hematopoietic disorders – Malignancies

– Immunodeficiency disorders

– Lysinuric protein intolerance (Lysinuric 단백질 불내성증) – Acute silicosis and other inhalational syndromes

(68)

Pulmonary Alveolar Proteinosis (PAP)

폐포단백증

• Congenital PAP

g

– Rare cause of immediate-onset neonatal

respiratory distress

– Multiple mutation

p

• ABCA3 (ATP-binding protein member A3) : most frequent

– Localized to lamellar body

– Involved in transport of surfactant components

• SP-B (surfactant protein B)

– Autosomal recessive

– Frameshift mutation of SP-B

• SP-C (surfactant protein C) • GM-CSF

• GM-CSF receptor (GM-CSF/IL-3/IL-5) β chain • GM CSF receptor (GM CSF/IL 3/IL 5) β chain

(69)

Pulmonary Alveolar Proteinosis (PAP)

폐포단백증

형태학적 특징

• 형태학적 특징

(1) Peculiar homogeneous granular precipitate (Periodic (1) Peculiar, homogeneous, granular precipitate (Periodic

Acid-Schiff positive) within alveoli

→ focal-to-confluent consolidation of large area of lung but no inflammation

no inflammation

→ ↑↑↑ size and weight of lung (2) EM (전자현미경) :

• Alveolar contents consists of necrotic alveolar macrophage, type II pneumocytes, amorphous precipitates, and lamellar osmiophilic bodies

(70)

Pulmonary Alveolar Proteinosis

The alveoli are filled with a dense, amorphous, protein-lipid granular precipitate, while the alveolar walls are normal.

(71)

(72)

Pneumoconioses (진폐증)

(

)

1. 정의:

• Mineral dust의 inhalation에 대한 non-neoplastic lung reaction을 의미한다.

– Coal dust (탄분): anthracosis

( 소) ( 폐 )

– Silica (규소): silicosis (규폐증)

– Asbestos (석면): asbestosis (석면폐증)Asbestos (석면) asbestosis (석면폐증) – Beryllium (베릴륨): berylliosis

– less common :

• Iron dust (siderosis), tin dust (stannosis), barium dust

( )

(73)

Pneumoconioses

• Pneumoconiosis의 3 general tissue

response ★

1) Fibrotic nodule (silicosis에서 주로)

)

(

)

2) Interstitial fibrosis (asbestosis 주로)

(74)

Pneumoconioses (진폐증)

(

)

2. Pneumoconiosis의 development에 관여하는 factors

(1) lung, airway에 잔류하는 dust의 양 (2) particle의 size, shape, buoyancy

(most dangerous particle : 1～5 ㎛ in diameter) (3) particle의 solubility와 physiochemical reactivity ( )

(4) additional effects of other irritants → mucociliary apparatus에 영향 줌 (e.g. tobacco smoking)

3 Particle의 solubility와 cytotoxicity는 size에 영향을 받는다 3. Particle의 solubility와 cytotoxicity는 size에 영향을 받는다

(1) size가 작으면

• surface area-to-mass ratio가 크고, pulmonary fluid에서 더 빨리 toxic level에 도달 (acute lung injury)

level에 도달 (acute lung injury)

(2) size가 크면

• dissolution이 안되고 오랫동안 폐실질에 남아 fibrosing collagenous pneumoconiosis생김 (silicosis)

4. Lung에 잔류하는 amount of dust를 결정짓는 factors

(1) air의 dust concentration

(2) 의 d i

(2) exposure의 duration

(75)

Coal workers’ pneumoconiosis

Coal workers pneumoconiosis

(탄광부 진폐증)

Coal mining (탄광업)

(1) Asymptomatic anthracosis (탄분증)

(2) Simple coal workers' pneumoconiosis (단순형)

(2) Simple coal workers pneumoconiosis (단순형)

with little to no pulmonary dysfuction

( )

(3) Complicated CWP or progressive massive fibrosis

(복잡형, 진행형), with compromised lung function

(4) Caplan syndrome (= RA + pnemoconiosis)

(76)

Coal workers’ pneumoconiosis (탄광부 진폐증)

(1) Asymptomatic anthracosis (탄분증)

1) Pigment accumulate without a perceptible

cellular reaction

)

2) Microscopic finding

i) Inhaled carbon particle is engulfed by alveolar or

interstitial macrophage then, accumulate

connective tissue & lymphatics

ii) Linear streaks, aggregates of anthracotic pigment

along pulmonary lymphatics & pulmonary LN ★

(77)

Coal workers’ pneumoconiosis

(탄광부 진폐증)

(2) Simple coal workers' pneumoconiosis (단순형)

1) Accumulations of macrophages with little to no pulmonary 1) Accumulations of macrophages with little to no pulmonary

dysfunction 2) Coal macules 2) Coal macules

i) 1～2㎜, carbon-laden macrophages로 구성 ★

ii) upper lobe, lower lobe upper zone의 respiratory bronchiole 주변에 주로 보임 → 시간이 지나면 주변 alveoli가 dilation → centrilobular emphysema

3) Coal nodules : coal macule + delicate network of collagen fibers 4) 10%미만에서 PMF로 진행 ★

(78)

Simple coal workers’

Simple coal workers

pneumoconiosis

In addition to diffusely increased This thin section of lung pigmentation, the lung parenchyma

shows well-demarcated black nodules.

demonstrates multiple small, circumscribed black nodules

(79)

Simple coal workers’ pneumoconiosis

The coal dust macule is

characterized by focal interstitial pigment deposition.

In this example destruction of the Coal nodule In this example, destruction of the

adjacent alveolar septa, termed focal emphysema, is also seen.

• collarette of pigmented macrophages (“medusa-head” appearance)

(80)

Coal workers’ pneumoconiosis

(탄광부 진폐증)

(3) Complicated CWP or progressive

i

fib

i (복잡형 진행형)

massive fibrosis (복잡형, 진행형)

)

1) Intensely blackened scar larger than 2cm,

multiple, dense collagen and pigment with

necrotic center (local ischemia) ★

2) Extensive fibrosis compromised lung

2) Extensive fibrosis, compromised lung

(81)

Complicated coal workers’ pneumoconiosis

A large black irregular fibrotic A large black irregular fibrotic

lesion has destroyed the perihilar lung parenchyma.

The upper lobe Æ confluent irregular area of fibrosis + central cavitation

(82)

Coal workers’ pneumoconiosis (CWP)

Å haphazardly arranged collagen bundles are

interspersed with abundant interspersed with abundant pigment.

At higher magnification, the black carbonaceous core of this

ferruginous, or pseudoasbestos, body is evident.

Partial polarization shows a mixture of faintly and brightly birefringent particles superimposed on black pigment

(83)

Coal workers’ pneumoconiosis

(탄광부 진폐증)

• Caplan syndrome

p

y

1) Coexistence of rheumatoid arthritis with

i

i (di ti

ti

l

d l )

pneumoconiosis (distinctive pulmonary nodule)

2) Asbestosis Silicosis에서도 생김

2) Asbestosis, Silicosis에서도 생김

3) Central necrosis surrounded by fibroblasts,

macrophages, and collagen

(84)

Coal workers’ pneumoconiosis

(탄광부 진폐증)

임상경과

★

(탄광부 진폐증)

• 임상경과

★

1) PMF (progressive massive fibrosis)

• CWP와 silicosis에서 가장 흔하다

• 이것이 생기면 exposure를 막아도 진행한다.

• 진행되면 ↑pulmonary dysfunction, pulmonary hypertension, cor pulmonale

2) No convincing evidence that coal duct increase susceptibility to tuberculosis (cf, silicosis)

3) Some evidence that exposure to coal dust increase the incidence of chronic bronchitis and emphysema, in

dependent of smoking dependent of smoking

3) No compelling evidence that CWP in absence of smoking predisposes to cancer

(85)

Silicosis (규폐증)

( ) ( )

(1) Crystalline silicon dioxide (silica)의 흡입에 의한 lung disease

(2) 모래연마공이나 광부에게 흔하다.

(3) 현재 most prevalent chronic occupational disease in the world (4) 수십 년간 노출된 뒤, 천천히 진행하는 nodular fibrosing

pneumoconiosis로 나타난다.

(5) 드물게 수개월 또는 몇년간 심하게 노출되어도 발생

– Acute silicosisAcute silicosis

• Accumulation of abundant lipoproteinaceous material within alveoli • alveolar proteinosis와 형태학적으로 동일

(86)

Silicosis (규폐증)

Silica

• Silica

1) Crystalline form : more fibrogenic ★

• quartz (석영) : most commonq ( 영) • Crystobalite

• Tridymite

2) Amorphous form

• Pathogenesis

g

Macrophages ingest silica particle

A ti

ti

d

l

f

di t

→ Activation and release of mediators

(IL-1, TNF, fibronectin, lipid mediators,

oxygen-derived free radicals, fibrogenic cytokines)

(87)

Silicosis (규폐증)

형태

– Early stage:

• Tiny barely palpable discrete nodular lesion형태로 주로 upper zone에 • Tiny, barely palpable, discrete nodular lesion형태로 주로 upper zone에

생김

– Progression:

• 합쳐져서 hard collagenous scar형성

• Some nodule → superimposed tuberculosis or ischemia → central softening and cavitation

Fibrotic lesion in the hilar lymph nodes and pleura – Fibrotic lesion in the hilar lymph nodes and pleura – Egg shell calcification :

• X-ray에서 thin sheets of calcification in lymph node

– Continuous progression → expansion and coalescence of lesion → progressive massive fibrosis (PMF)

– Histology :

• Concentric layers of hyalinized collagen surrounded by a dense capsule of more condensed collagen

capsule of more condensed collagen

(88)

Silicosis (규폐증)

• Clinical course

– Most patients do not develop shortness of breath

until late in the course (progressive massive

fibrosis, PMF)

– Increased susceptibility to tuberculsis

D i f ll di t d i it

• Depression of cell-mediated immunity

• Crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteriap g p g y y

(89)

Silicosis (규폐증)

Grossly circumscribed areas of Grossly, circumscribed areas of

nodular fibrosis are firm and slate gray in appearance.

At low magnification, silicotic nodules are sharply circumscribed and

Several coalescent collagenous silicotic nodules

are sharply circumscribed and densely collagenous (Masson trichrome stain).

silicotic nodules

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 10 April 2006 08:59 AM)

(90)

Silicosis Silicosis.

A higher magnification view of a silicotic

nodule shows the typical whorled appearance.

M h t t th i h f

Macrophages are present at the periphery of the nodule.

The lung parenchyma underlying

Silicosis. Silicotic nodules within a lymph node characteristically contain centrally dense hyalinized collagen surrounded by

The lung parenchyma underlying the pleura is a common location for silicotic nodules.

dense, hyalinized collagen surrounded by concentric whorls of more loosely arranged collagen bundles.

(91)

Advanced silicosis

Conglomerate silicosis.

confluent fibrosis in the upper lobe (arrow).

Advanced silicosis

• Scarring has contracted the upper lobe into a small dark mass (arrow).

(92)

Asbestos-related diseases

(1) Asbestos (석면)

1) Fib 형태의 t lli h d t d ili t 의 일종 Æ fib i 1) Fiber형태의 crystalline hydrated silicates의 일종 Æ fibrogenic 2) act as tumor initiator and tumor promoter → 다른 toxic

chemical이 함께 흡수되면 synergy → ↑cancer risk 3) Pathogenesis

• SerpentineSerpentine

① more soluble, curled & flexible fiber

② chrysotile (온석면) : 산업부문에 사용되는 것의 대부분을 차지

• Amphibole Æ more pathogenic, induction of mesothelioma

① Straight, stiff, brittle fiber

② Amphibole의 pathogenesis에 관여하는 factor

② p p g

» Aerodynamic properties : align in air stream

» Solubility : less soluble, penetrate epithelial cell, reach interstitium

» Length of fiber : longer and thinner

(93)

Asbestos-related diseases

Asbestos related diseases

(2) 관련된 질환들 ★

1) L li d fib l l diff l l fib i

1) Localized fibrous plaque or rarely diffuse pleural fibrosis

2) Pleural effusion

3) Parenchymal interstitial fibrosis (Asbestosis, 석면증)

4) Bronchogenic carcinoma ★

• Most common associated malignancy (5배)

• Concomitant cigarette smoking이 risk 증가 (55배)시킴 (but not that of th li )

mesothelioma)

5) Mesothelioma (1000배) ★

Pleural and peritoneal • Pleural and peritoneal

• Rare incidence (2~17/100만명): Mesothelioma less than bronchogenic carcinoma

6) Laryngeal and other extrapulmonary neoplasms (including colon carcinomas)

(94)

Asbestos-related diseases

(3) 형태

1) Diffuse pulmonary interstitial fibrosis

• asbestos body를 제외하고는 다른 diffuse interstitial fibrosis와 구별 안됨

2) Asbestos bodies

i) golden brown, fusiform or beaded rods with a translucent center

ii) asbestos fibers + coated with iron containing proteinaceous materials ii) asbestos fibers + coated with iron-containing proteinaceous materials

* Ferruginous bodies :

• iron-containing proteinaceous materials without asbestos core

Asbestos bodies in a sputum

beading and knobbed ends (arrow).

cytology specimen

(95)

Asbestos-related diseases

(3) 형태

3) Fibrosis begins around respiratory bronchioles and alveolar duct → distorted architecture Æ honeycombing (similar to UIP)

4) lower lobe 의 subpleural area에서 시작 중엽,상엽으로 퍼짐 (↔ CWP, silicosis)

( CWP, silicosis)

5) 동시에 visceral pleura도 fibrous thickening이 일어남 6) Pleural plaque

• Most common manifestation

• Well circumscribed plaque of dense collagen containing • Well circumscribed plaque of dense collagen containing

calcium

• Ant & posterolateral aspects of parietal pleura, dome of diaphragm에 주로 생김

(96)

Asbestosis

(석면폐증)

Fibrocalcific plaques on the pleural Fibrocalcific plaques on the pleural surface of the diaphragm.

(Courtesy of Dr. John Godleski, Brigham and Women's Hospital, Boston, MA.)

The lower lobe parenchyma shows patchy fibrosis.

Visceral pleural thickening is also evident (arrow).

(97)

Berylliosis (베릴륨증)

y

(

)

• Fume of metallic beryllium, its oxides, alloys, salt, airborne dust → heavy exposure → acute pneumonitis

→ heavy exposure → acute pneumonitis • Long low-dose exposure

→ pulmonary and systemic granulomatous lesion (sarcoidosis와 구별이 매우 힘들다)

• Heavy beryllium exposure → ↑incidence of lung cancer Ch i b lli i

• Chronic berylliosis

1) Cell-mediated immunity에 의해 induced됨

2) 노출된 노동자 중 20%에서만 생기므로 immune response가 시작되려 면 genetic susceptibility가 있어야 한다.

3) Non-caseating granuloma in lungs, lymph nodes, spleen, liver, kidney, adrenal

(98)

Berylliosis

Lik id i h i b lli i d

• Like sarcoidosis, chronic berylliosis produces

(A) variable fibrosis and

(B) distinct granulomas with giant cells.

Th b ti f l h ti i fl ti

• There may be a suggestion of more lymphocytic inflammation, but this is not sufficiently reliable to be useful diagnostically.