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atho|ogy of Norma| Lung, Lung

Cancer, CCD, and A|rways D|sease


Andrew Churg, Mu
ueparLmenLs of aLhology
unlverslLy of 8rlush Columbla
and vancouver Ceneral PosplLal
vancouver, 8C
achurg[mall.ubc.ca

D|sc|osure
l have no conlcLs of lnLeresL Lo dlsclose
Cb[ecnves
1o revlew normal lung anaLomy
1o revlew Lhe paLhology of lung cancer
1o revlew Lhe paLhology of CCu and AsLhma
1o revlew oLher forms of alrways dlsease
1op|cs
normal lung anaLomy
Lung cancer
CCu
Alrway dlseases
AsLhma
lnfecuous bronchlollus
8ronchopneumonla
8ronchlollus obllLerans (consLrlcuve bronchlollus)
Bronchovascular bundle
Normal lung (formalin
vapor fixed)
Bronchovascular
bundle: bronchi
and pulmonary
artery branches run
together
01-3517
Bronchovascular bundle
Normal bronchus
Bronchus defined
by presence of
cartilage
Bronchial glands
normal Lung
Bronchioles
Interlobular
septum
Pleura
M8
09-12948
Normal membranous bronchiole:
Bronchioles are defined by lack of cartilage
Pulmonary
artery branch
Membranous bronchiole
Alveoli
MB
RB
RB
AD
1H-75
AD
Membranous bronchiole (MB): continuous wall
Respiratory bronchiole (RB): partially alveolated wall
Alveolar duct (AD): completely alveolated wall

Alveoli
Type 2 Cell
Capillary
Alveolus
Alveolus
Parenchyma
LUNG CANCLk

Common 1ypes of Lung Cancer
usually smoklng relaLed
Squamous cell carclnoma
Adenocarclnoma
8ronchoalveolar carclnoma (adenocarclnoma ln slLu)
Small cell carclnoma
Large cell carclnoma
noL smoklng relaLed
Carclnold
A 6S year o|d man w|th a 40 pack-yr smok|ng h|story presents
w|th hemoptys|s and |s found to have a mass |nvo|v|ng the r|ght
upper |obe bronchus. Cn the r|ght |s a p|cture of the b|opsy. 1he
correct d|agnos|s |s:

1. Squamous cell carclnoma
2. Small cell carclnoma
3. Adenocarclnoma
4. noL a carclnoma of any
klnd
Squamous Ce|| Carc|noma
Not Lhe mosL common Lype of lung cancer
SLrongly smoklng relaLed
usually falrly bulky cenLral leslons
usually accesslble by bronchoscopy
Cood yleld on washlng/brushlng/spuLum cyLology
May cause obsLrucuve (golden) pneumonla behlnd
Lumor
May cause bronchlecLasls behlnd Lumor
May cause lobar collapse
Squamous cell ca
with lower lobe
collapse and distal
bronchiectasis
C82-79
Collapsed
lower lobe
Bronchiectasis
Tumor
Squamous Ce|| Carc|noma
aLhologlc denluon of squamous cell carclnoma
Cells make keraun and/or
Cells are connecLed by lnLercellular brldges
18308-1
Squamous cell ca
Keratinized
cells
18308-3
Squamous cell ca
Intercellular bridges
Adenocarc|noma
1he mosL common Lype of lung cancer
MosL adenocarclnomas are smoklng-relaLed
Powever, adenocarclnoma ls Lhe common Lype of lung
cancer ln non-smokers
Many adenocarclnomas are perlpheral leslons
Cen noL accesslble by bronchoscopy
Core needle blopsy or lnA oen needed for lnlual
dlagnosls
Adenocarcinoma
Peripheral,
subpleural lesion
Adenocarc|noma
aLhologlc denluon of adenocarclnoma
Makes glands and/or
SecreLes mucln
Mucln can be demonsLraLed by AS or muclcarmlne sLaln
(or someumes on P&L)
163327-1
Adenocarcinoma
Glands
Mucin
8ronchoa|veo|ar Carc|noma (8AC) =
Adenocarc|noma |n S|tu (AIS)
usually perlpheral leslons
ure 8AC appears as ground glass nodules on C1
8elleved Lo be Lhe ln slLu phase of adenocarclnoma
new A1S/L8S classlcauon (! 1hor Cncol 2011)
suggesLs uslng Adenocarclnoma ln slLu" lnsLead of 8AC
8y denluon Lumor cells grow along alveolar walls
(leplJlc qtowtb)
8y denluon Lumor cells do noL lnvade
06-3659-2
BAC: Appears as a ground glass opacity
The greater the amount of solid
opacity, the greater the likelihood of
invasive carcinoma
06-3659
BAC/AIS
06-3659-2
BAC/AIS: Lepidic growth and mild fibrosis of underlying alveolar walls
06-3659-4
BAC/AIS: Lepidic growth/cytologic atypia
vs07-111-1
Needle core bx of peripheral lung nodule in a cigarette smoker
vs07-111-2
Tumor cells show lepidic growth
1he correct d|agnos|s for the |mages |n the |ast
2 s||des |s:
1. ALyplcal adenomaLous hyperplasla (AAP)
2. 8ronchoalveolar carclnoma/adenocarclnoma ln slLu
(8AC/AlS)
3. Adenocarclnoma, nCS
4. MallgnanL buL wheLher Lhls ls a 8AC/AlS or lnvaslve
adenocarclnoma cannoL be deLermlned on Lhls Lype
of blopsy (compleLe exclslon requlred)
8AC]AIS and Adenocarc|noma
8AC belleved Lo be Lhe precursor leslon of many (?
all) perlpheral adenocarclnomas
Adenocarclnomas are lnvaslve by denluon
Cver ume 8AC develops cenLral scar and Lhen cenLral
lnvaslve adenocarclnoma
lncreaslng evldence LhaL perlpheral
adenocarclnomas LhaL are largely 8AC wlLh less Lhan
3mm of cenLral lnvaslon can probably be LreaLed by
wedge resecuon raLher Lhan lobecLomy (however,
Lhls ldea ls somewhaL conLroverslal)
Survival Using Sub-lobar Resection for Pure BAC (AIS)
D Arenberg Chest 2007
roposed new
lASLC/A1S/L8S
Classlcauon of
Adenocarclnomas

(1ravls eL al: ! 1horaclc Cncol
2011)
roposed New IASLC]A1S]LkS C|ass|hcanon of
Adenocarc|nomas
(1rav|s et a|: I 1horac|c Cnco| 2011)
lor leslons < 3cm ln dlameLer
nonmuclnous 8AC now classled as adenocarclnoma ln slLu"
Can be LreaLed by wedge exclslon
SollLary Lumors wlLh predomlnanLly lepldlc growLh and less
Lhan 3mm of lnvaslon classled as mlnlmally lnvaslve
adenocarclnoma"
SollLary Lumors wlLh predomlnanLly lepldlc growLh and more
Lhan 3mm of lnvaslon classled as lepldlc predomlnanL
adenocarclnoma
Muclnous 8AC vlewed as lnvaslve muclnous adenocarclnomas
Pure lepidic growth = BAC/AIS
Lepidic growth, <5mm invasion =
Minimally invasive adenoca

Lepidic growth, >5mm
invasion = Lepidic
predominant adenoca
<5mm
>5mm
vS11-20176
Adenocarcinoma with peripheral lepidic growth and
< 5mm of invasion: Under new proposed classification:
Minimally Invasive Adenocarcinoma
1mm lnvaslve focus
1mm focus of lnvaslon: CorrecL ux: Mlnlmally lnvaslve
adenocarclnoma (or 8AC wlLh 1mm of lnvaslve
carclnoma)
1mm focus of lnvaslon: CorrecL ux: Mlnlmally lnvaslve
adenocarclnoma (or 8AC wlLh 1mm of lnvaslve
carclnoma)
As yeL unclear wheLher Lhese Lumors can be LreaLed
by wedge exclslon alone
Solld
aplllary
Mlcropaplllary Aclnar
From Yoshizawa et al: Mod Path 2011
Plgh grade
Plgh grade
lnLermedlaLe grade
lnLermedlaLe grade
SLage 1 Adenocarclnoma: ulsease lree Survlval by PlsLologlc auern
From Yoshizawa et al: Mod Path 2011
Low grade (lncl AlS)
lnLermedlaLe grade
Plgh grade
Sma|| Ce|| Carc|noma
SLrongly smoklng relaLed
usually cenLral leslons (perlpheral leslons
uncommon)
usually accesslble by bronchoscopy
Cood yleld on washlng/brushlng/spuLum cyLology
usually wldespread aL presenLauon
rlmary leslon may be very small
Surgery usually conLralndlcaLed
Sma|| Ce|| Carc|noma
aLhologlc denluon:
Cells usually 2-3 umes slze of a lymphocyLe
Cells have very hlgh nuclear: cyLoplasmlc rauo
nuclel oen mold Lo each oLher
usually very hlgh mlLouc raLe
usually exLenslve necrosls of Lumor
Clder name of oaL cell carclnoma" no longer used
77-9368-2
Small cell carcinoma
77-9368
Small cell carcinoma
Small cells
Scanty cytoplasm
High N:C ratio
Fine stippled chromatin
Small cell carcinoma
Squamous cell carcinoma
Large Ce|| Carc|noma
SLrongly smoklng relaLed
1umors usually cenLral
usually accesslble by bronchoscopy
Cood yleld on washlng/brushlng/spuLum cyLology buL
dlsuncuon from adenocarclnoma on cyLology alone ls
dlmculL
8y denluon relauvely large cells LhaL do noL have
Lhe feaLures of squamous or adenocarclnoma
8y elecLron mlcroscopy [usL very poorly dlerenuaLed
squamous or adenocarclnomas

169670-1
Large cell carcinoma
169670-2
Does not have features of squamous or adenocarcinoma
Why the C|d atho|og|c D|agnos|s "Sma|| Ce|| vs
Non-Sma|| Ce|| Carc|noma" Isn't Good Lnough
Any More -
8AC/AlS can be LreaLed by wedge resecuon
Small cell carclnoma LreaLed by chemoLherapy/
radlauon raLher Lhan surgery
MosL adenocarclnomas and squamous cell
carclnomas have meLasLaslzed aL ume of
presenLauon and chemoLherapy ls Lhe only
LreaLmenL opuon
Why the C|d atho|og|c D|agnos|s "Sma|| Ce|| vs
Non-Sma|| Ce|| Carc|noma" Isn't Good Lnough
Any More
lncreaslngly LargeLed Lherapy depends on cell Lype
Adenocarclnomas may respond Lo:
LCl8 lnhlblLors (lressa, 1arceva)
emeLrexed (AllmLa)
Anu-vLCl Lherapy (8evaclzumab)
Crlzounlb for Lumors wlLh ALk-LML4 Lranslocauon
Why the C|d atho|og|c D|agnos|s "Sma|| Ce|| vs
Non-Sma|| Ce|| Carc|noma" Isn't Good Lnough
Any More -
lncreaslngly LargeLed Lherapy depends on cell Lype
Squamous cell carclnomas Lyplcally do noL show LCl8 or
k8AS muLauons
Squamous cell carclnomas may bleed masslvely wlLh anu-
vLCl Lherapy (8evaclzumab)
Squamous cell carclnomas oen harbor lCl81 muLauons:
LargeLed Lherapy belng developed
ko|e of Immunoh|stochem|stry |n
Subc|ass|fy|ng r|maryLung Cancers
Squamous Adeno Small Cell
p63+ 11l-1+ 11l-1+
Ck3/6+ p63- Chromogranln+
11l-1- Ck3/6- SynapLophysln+
Ck7- Ck7+ Cu36+
napsln- napsln + napsln-

Ck = cyLokeraun
ko|e of Immunoh|stochem|stry |n
Subc|ass|fy|ng Lung Cancers
Sorung ouL small cell from non-small cell carclnoma
Separaung squamous cell from adenocarclnoma
lmmooocbemlstty most osefol wbeo tbe blopsy ls
vety smoll ot tomot pootly Jl[eteouoteJ
Also useful for sorung ouL prlmarles from meLs
lf Lumor noL classlable by lmmunochemlsLry, Lhen
Lhe Lerm non-small cell carclnoma" ls sull
approprlaLe
Poorly differentiated carcinoma on bx
?Features suggestive of squamous cell
Tumor is p63 and CK5/6 +
Confirms diagnosis of
squamous cell ca
p63
CK5/6
Malignant appearing
cells in pleural fluid
cytology specimen
Tumor cells are TTF-1 +
Indicates that this is
metastatic from a lung
adenocarcinoma
11l-1
Carc|no|d
MosL common lung Lumor aer bronchogenlc
carclnoma
noL smoklng relaLed
Cells are neuroendocrlne cells and conLaln
neurosecLory granules
SeroLonln (carclnold syndrome -- rare)
AC1P (Cushlng's syndrome - rare)
All carclnolds are mallgnanL
1yplcal" carclnold = low grade, 90 10 yr survlval
ALyplcal" carclnold = hlgh grade, 33-60 10 yr survlval
Carc|no|d - atho|ogy
usually cenLral endobronchlal Lumors
usually slow growlng: produce bronchlecLasls behlnd
Lumor
Always lnvade bronchlal wall
CannoL cure by curremng
8y mlcroscopy a varleLy of neuroendocrlne" growLh
pauerns
8land appearlng cells, round or splndled
very vascular Lumors -Lend Lo bleed when blopsled
8y lmmunochemlsLry posluve for synapLophysln,
chromogranln, 11l-1, Cu36
Carcinoid
Bronchial wall
Tumor in distended bronchus
87-3332
Distal
bronchiectasis
Carcinoid

Carcinoid Note marked vascularity


Carcinoid Synaptophysin
CD56
CCD Lno|og|es
Clgareue smoke (mosL cases ln norLh Amerlca)
Cccupauonal dusL exposure (for ex, coal mlners)
Cccupauonal fume exposure
? Plgh levels of amblenL alr polluuon
Cooklng wlLh blomass fuels
Anatom|c]C||n|ca| Lnnnes |n CCD
Lmphysema
Small alrway remodellng (small alrway dlsease)
8ronchlal mucus gland hyperplasla wlLh excess
mucus producuon (chronlc bronchlus)
vascular remodellng wlLh pulmonary hyperLenslon
AcuLe exacerbauon
urely cllnlcal enuLy-no clear anaLomlc correlaLe
Ac|n| and Lobu|es
Aclnus conslsLs of all alrways and parenchyma dlsLal Lo
Lhe lasL generauon (Lermlnal) membranous bronchlole
Lobule conslsLs of all ussue bounded by lnLerlobular
sepLa
up Lo 6 aclnl are found ln Lhe cenLer of Lhe lobule, hence
cenLrllobular" and cenLrlaclnar" are roughly equlvalenL
Aclnl are noL dlagnosucally useful buL lobules are
Plgh resoluuon C1 scans can see lobules
Many dlseases have dlsuncL dlsLrlbuuons wlLhln Lhe lobule
01-3517
Lobule (case of lymphangitic ca)
Pulmonary Lobule: Gough section
Interlobular septum
Bronchovascular
bundle
152314
Interlobular septa
Lobule
Pleura
Lmphysema: Dehn|non
A condluon of Lhe lung characLerlzed by abnormal
permanenL enlargemenL of alrspaces dlsLal Lo Lhe
Lermlnal bronchlole, accompanled by desLrucuon of
Lhelr walls and wlLhouL obvlous gross brosls
Centr||obu|ar (Centr|ac|nar)
Lmphysema
Poles are ln cenLers of lobules (aclnl) wlLh
surroundlng normal lung
upper zone predomlnanL
Classlc clgareue smoke-assoclaLed form of
emphysema
CenLrllobular Lmphysema
u807-181
Lmphysema: Centr||obu|ar
(centr|ac|nar)
CenLrllobular (cenLrlaclnar) Lmphysema

CenLrllobular Lmphysema
Emphysematous area =
destroyed RB
M8
88
Surrounding normal
parenchyma
MB=membranous bronchiole
RB=respiratory bronchiole
an|obu|ar (anac|nar) Lmphysema
Poles LhroughouL lobule (aclnus)
usually lower zone predomlnanL
AssoclaLed wlLh -1-anuLrypsln declency
AssoclaLed wlLh clgareue smoklng

Panlobular Emphysema
anlobular Lmphysema
A37-3
arasepta| Lmphysema
(D|sta| ac|nar emphysema)
Poles wlLh walls perpendlcular Lo Lhe pleura
Can have some degree of brosls ln walls
Luologles uncerLaln buL seen ln smokers
Also assoclaLed wlLh sponLaneous pneumoLhorax ln
young (nonsmoklng) adulLs
Lmphysema: arasepta|
Pleura
Pleura
1he best way to d|agnose emphysema |s
by:
1. vA1S blopsy
2. 1ransbronchlal blopsy
3. Core needle blopsy
4. C1 scan
Comments re Lmphysema
C1 scan ls a very accuraLe meLhod of dlagnoslng
emphysema
aLhologlcally emphysema ls besL dlagnosed on
gross speclmens of resecLed lobes or lungs or
auLopsy speclmens
8lopsy speclmeos ote oot soltoble fot evoloouoq
empbysemo
no one does a surglcal lung blopsy Lo dlagnose
emphysema!
C|gareue Smoke-Induced A|rway D|sease
Smoker's resplraLory bronchlollus (88): resplraLory
bronchloles
Small alrway remodellng (small alrway dlsease):
predomlnanLly membranous bronchloles, and Lo
some exLenL resplraLory bronchloles
Chronlc bronchlus: large alrways (bronchl)
C84-64
Smoker's 8esplraLory 8ronchlollus (88")
8esplraLory
8ronchlole
Smokers
macrophages
09-12948
Normal membranous bronchiole Small Alrway 8emodellng - Clgareue Smoker
03-2738
03-2738
Small Alrway ulsease--Clgareue Smoker
03-2738
Small Alrway 8emodellng ln Clgareue Smokers
1. Narrowed or obliterated lumen
2. Increased fibrous tissue in airway
wall leading to thick airway wall
3. Inflammation in airway wall
4. Mucus plugs in lumen

Result: Decreased flow/turbulent
flow
Mucus plug
S|gn|hcance of C|gareue Smoke-
Induced A|rway D|sease
Small alrway remodellng ls an lmporLanL cause of
alrow obsLrucuon
cbtoolc btoocblus ptobobly Joes oot ptoJoce oltfow
obsttocuoo (coottovetslol)!
uened enurely by spuLum producuon
AssoclaLed wlLh cllnlcal exacerbauons (lnfecuous eplsodes
wlLh funcuonal deLerlorauon)
I|nd|ngs |n Asthma
1hlckened alrway basemenL membrane
MosL conslsLenL ndlng (ln large alrways)
lncreased alrway smooLh muscle
MosL conslsLenL ndlng ln large and small alrways
Loslnophlls ln alrway wall or lumen
uenuded alrway eplLhellum
lncreased gobleL cells ln alrway eplLhellum
Mucus plugs ln alrways
wblcb feototes ote pteseot lo oo loJlvlJool cose ls vety
votloble
auenL dylng ln sLaLus asLhmaucus
Mucus plug
ln lumen
1hlck 8M
AC06-0239
Increased
smooth muscle
Increased airway
smooth muscle
Thick
basement
membrane
Airway
epithelium
denuded
Asthma: eosinophils in airway wall
Infecnous 8ronch|o||ns
ln lmmunocompeLenL pauenLs: Wlde range of agenLs buL especlally seen
wlLh:
Mycoplasma
vlral lnfecuons of all Lypes
very varlable morphology
AcuLe lnammauon
Chronlc lnammauon
AcuLe lnammauon ln lumen, chronlc lnammauon ln wall
Alrway eplLhellal damage
Morphology usually does noL lndlcaLe agenL unless vlral lncluslons found
CulLure or serology cruclal
lmmunohlsLochemlsLry someumes helpful (vlruses)
vlral lncluslons more commonly seen ln lmmunocompromlsed pauenLs
Influenza - bronchiolitis
6C-77
Mns ln lumen
uamaged alrway
eplLhellum
Chronlc lnammaLory cells ln alrway
wall
vA06-90
Perpes slmplex -
necrouzlng alrway
cenLered leslon
M8
lmmunocompromlsed pauenL
Herpes simplex
Immunohistochemistry
Long 1erm Seque|ae of Infecnous
8ronch|o||ns
8eporLed long Lerm uncommon (morphologlc)
sequelae
8ronchlollus obllLerans (lncl Swyer-!ames syndrome)
8ronchlecLasls
Lung abcess
lnLersuual brosls
8eporLed long Lerm cllnlcal sequelae
Alrway hyper-reacuvlLy/asLhma
8ronchopneumon|a
1he ulumaLe lnfecuous bronchlollus
lnammaLory process sLarLs ln/around bronchloles,
spreads Lo parenchyma
aLhology
lllllng of bronchlolar lumens and parenchyma by
neuLrophlls (early), macrophages (laLe)
c82-363
8ronchopneumonla
Yellow = bronchioles
containing pus
Red = inflammation
& congestion in
parenchyma
v82-92
8ronchopneumonla
M8
PMNs
M8
Constr|cnve 8ronch|o||ns
(8ronch|o||ns Cb||terans)
Luologles
lume lnhalauon (example, farmer's lung)
Collagen vascular dlsease, esp 8A
osL-lnfecuous (example, Swyer-!ames syndrome)
lnammaLory bowel dlsease
urug-lnduced
AssoclaLed wlLh bronchlecLasls (especlally cysuc brosls)
Lung LransplanLauon (8C syndrome)
ldlopaLhlc
rogresslve, xed alrow obsLrucuon
Alr-Lrapplng on C1 buL brouc bronchloles are Loo small
Lo be seen on lmaglng
ConsLrlcuve bronchlollus ln 8A
CourLesy ur. nesLor Muller
Constr|cnve 8ronch|o||ns - atho|ogy
narrowed or obllLeraLed alrway lumen a conslsLenL
ndlng alrow obsLrucuon
Larly: lnammaLory cells or granulauon ussue ln
lumen
LaLe: Collagen deposluon beLween eplLhellum and
smooLh muscle
n8: CompleLely obllLeraLed bronchloles appear as
scars on P&L
oslly mlsseJ/JlsmlsseJ os ooospeclfc scots
losuc stolos ctoclol to mokloq tbe Jloqoosls
09-12948
Normal membranous bronchiole:
Pulmonary
artery branch
Membranous bronchiole
Larly ConsLrlcuve 8ronchlollus ln 8A
Narrowed lumen
Granulation tissue
Cld ConsLrlcuve 8ronchlollus ? Secondary Lo MeLhoLrexaLe ? Caused by 8A
Dense collagen
between epithelium
and muscle
Markedly narrowed
lumen
What to 1h|nk About When an Cpen]
1horacoscop|c 8|opsy Appears to be
Comp|ete|y "Norma|" at I|rst G|ance
8lopsy mlssed Lhe leslon
aLhologlsL mlssed Lhe leslon
ConsLrlcuve bronchlollus (bronchlollus obllLerans)
8esplraLory bronchlollus wlLh lnLersuual lung dlsease
(88lLu)
ulmonary hyperLenslon
Changes of asLhma
no one does a blopsy Lo dlagnose emphysema!
1op|cs
normal lung anaLomy
Lung cancer
CCu
Alrway dlseases
AsLhma
lnfecuous bronchlollus
8ronchopneumonla
8ronchlollus obllLerans (consLrlcuve bronchlollus)