The lung

Novan Adi Setyawan

Pendahuluan
 Kelainan Kongenital

Pulmonary Hypoplasia

Foregut cyst

Pulmonary sequestration
 Atelektasis (Kolaps)

I. Resorption atelectasis
II. Compression atelectasis
III. Contraction atelectasis
 Acute Lung Injury & ARDS (Kerusakan difus alveolus)

❖ALI (udem pulmo nonkardiogenik) → hipoksemia

berat dan infiltrate pulmo bilateral, tanpa adanya
gagal jantung. Keadaan berat → ARDS
❖Patogenesis:
- Aktivasi endotel
- Adhesi dan ekstravasasi netrofil
- Akumulasi cairan intraalveolar dan pembentukan
membrane hialin
- Resolusi injury → nekrosis epitel, resorpsi edema
❖Prognosis > buruk : alkoholik kronik dan perokok
+ Klinis: dyspnea, takipnea,
meningkatnya sianosis dan
hipoksemia, gagal nafas dan
infiltrate bilateral difus pada
pemeriksaan radiologi
+ Terapi: ventilasi mekanik dan
terapi suportif
+ Pada survivor: fibrosis interstitial
dan penyakit paru kronis di
kemudian hari
 Edema Pulmo
Penimbunan cairan intersititial pada
alveolar spaces

Hemodynamic edema→ krn peningkatan

tek. Hidrostatik, paling banyak krn CHF.
Gamb: transudat intraalveolar, perdarahan
alveolar & hemosiderin makrofag

Nonkardiogenik edema→ krn injury pd

septum alveolar → eksudat peradangan
interstitial dan alveoli. Pneumonia >> jk
difus → ARDS
 OBSTRUCTION v.s RESTRICTION
OBSTRUCTION + RESTRICTION

Air or blood?
+ “Compliance”
Large or small?
Inspiration or Expiration?
+ “Infiltrative”

+ REDUCED lung VOLUME,

Obstruction is SMALL DYSPNEA, CYANOSIS
AIRWAY EXPIRATION
obstruction, i.e., wheezing + REDUCED GAS
TRANSFER
HYPEREXPANSION
Penyakit Paru Obstruktif
ENVIRONMENT
/ POLUTAN
Pneumokoniasis Coal Worker’s Pneumoconiosis

▪ “OCCUPATIONAL”
▪ “COAL MINERS LUNG”

▪ DUST OR CHEMICALS OR ORGANIC MATERIALS

▪ Coal (anthracosis)
▪ Silica
▪ Asbestos
▪ Be, FeO, BaSO4, CHEMO
▪ HAY, FLAX, BAGASSE, INSECTICIDES, etc.

Vary → little to no pulmonary dysfunction - complicated coal

workers’ pneumoconiosis/progressive massive fibrosis
develop emphysema and chronic bronchitis independent
of smoking.
Silicosis
caused by inhalation of proinflammatory crystalline silicon
dioxide (silica)
presents after decades of exposure as slowly progressing,
nodular, fibrosing pneumoconiosis
Asbestos – Related Diseases
Asbestos is a family of proinflammatory crystalline
hydrated silicates that are associated with pulmonary
fibrosis, carcinoma, mesothelioma, and other cancers.
Asbestos-related diseases include:
• Localized fibrous plaques or, rarely, diffuse pleural fibrosis
• Pleural effusions, recurrent
• Parenchymal interstitial fibrosis (asbestosis)
• Lung carcinoma
• Mesotheliomas
• Laryngeal, ovarian and perhaps other extrapulmonary
neoplasms, including colon carcinomas;
Marked by diffuse pulmonary interstitial fibrosis →
asbestos bodies: golden brown, fusiform or beaded
rods with a translucent center and consist of asbestos
fibers coated with an iron-containing proteinaceous
materia
asbestos can also act as a tumor initiator and promoter.
Some mediated by reactive free radicals
Drug Induced Lung Diseases
• An increasing number of prescription drugs→both acute and
chronic alterations in lung structure and function, interstitial
fibrosis, bronchiolitis obliterans, and eosinophilic pneumonia.
Ex: bleomycin → fibrosis

Radiation Induced Lung Diseases

• complication of therapeutic radiation of thoracic tumors (lung,
esophageal, breast, mediastinal)
• Acute radiation pneumonitis (lymphocytic alveolitis or
hypersensitivity pneumonitis); chronic (pulmonary fibrosis)
Pulmonary Involvement in Autoimmune Diseases

• (1) chronic pleuritis, with or without effusion; (2)

diffuse interstitial pneumonitis and fibrosis; (3)
RA intrapulmonary rheumatoid nodules; (4) follicular
bronchiolitis; or (5) pulmonary hypertension

Systemic • diffuse interstitial fibrosis (nonspecific interstitial

sclerosis pattern more common than usual interstitial
pattern) and pleural involvement
(scleroderma)

Lupus • patchy, transient parenchymal infiltrates, or

occasionally severe lupus pneumonitis, as well
erythematosus as pleurisy and pleural effusions
 Granulomatous Diseases
• Mainly LUNG (90%), but eye,
skin or ANYWHERE
• UNKNOWN ETIOLOGY
Sarcoidosis (IMMUNE, GENETIC factors)
• < 40 th, F>>M; B>>W

• immunologically mediated
→ exposure to inhaled
Hypersensitivity organic antigens
Pneumonitis • Alveolar walls = “extrinsic
allergic alveolitis” → Peny
Paru fibrosis kronis
SARCOIDOSIS

NON-Caseating
Granulomas are the RULE
“Asteroid” bodies within
these granulomas are
virtually diagnostic, but
hard to find
Pulmonary Infections
TUBERCULOSIS
NEOPLASMA PARU
EPIDEMIOLOGI

IARC,2008

GLOBOCAN 2018
 Squa Adeno Large Small
% % % %
Vincent, 1977 38 26.5 9.3 19.2

Suemasu, 1978 32.9 41.8 12.7

Hayata, 1980 40.8 39.8 9.6 8.7

Endardjo, 1990 32.3 38.9 1.5 5.6

GLOBOCAN 2018
 Carcinoma
Merokok (80%); radiasi (uranium);
Etiologi dan Patogenesis Asbestos; polusi udara

• >> terpapar asap rokok

SCC • Mutasi TP53 >>; 15 % ↓ g RB; ↑ EGFR1

• Berhub erat merokok

Small • ↓ TP53 (75-90 %); ↓ gRB (100%); ↑ g MYC family
cc

• Mayoritas tumor saat ini

• Mutasi reseptor tirosin kinase: EGFR, ALK, ROS, MET &
Adenoca RET; without → mutasi gen KRAS
 Lesi Prekursor

Diffuse idiopathic
Squamous atypical
adenocarcinoma pulmonary
dysplasia and adenomatous
in situ neuroendocrine cell
carcinoma in situ hyperplasia
hyperplasia

Klasifikasi

• Adenocarcinoma
(38%)
• Squamous cell
carcinoma (20%)
• Small cell carcinoma
(14%)
• Large cell carcinoma
(3%)
• Other (25%)
Goblet cell hyperplasia (A) basal cell hyperplasia (B squamous metaplasia (C).

squamous dysplasia (D) Carsinoma Insitu(CIS) (E) invasive squamous ca (F)

• 2/3 SCC occur in central location
• Strongly related to cigarette
smoking.
• 90 % of these tumor occur in
smoker
• FNA smear are usually cellular
cohesion, background of necrotic
debris
 Karsinoma Sel Skuamosa
• SITOLOGI • IMUNOHISTO
- nekrosis dan debris sel - MW Keratin
- sel terisolasi - Sitokeratin 5/6
- inti sentral ireguler - p40, p63
- hiperkromatik
- anak inti kecil 1-2
- sitoplasma lebar
- bentuk sel bizarre
Histologi Sitologi
The neoplastic cells can be round, A large tissue fragment composed of
oval, elongated into tadpole or tumor cells which have large nuclei
fiber cells with characteristic with macronucleoli, variation of
dense cytoplasm N/C ratio and dense cytoplasm
 Adenokarsinoma

1. Perifer, terbanyak dan disertai

stroma desmoplastik
2. Sentral atau endobronkial
3. Konsolidasi mirip
pneumonia difus
4. Penebalan pleura
merata
5. Latar belakang fibrosis
 Adenokarsinoma
SITOLOGI + IMUNOHISTO
- sel tunggal, morula, asini, papiler - AE1/AE3
- inti bulat/oval ditepi, kromatin - Cam 5.2
halus, anak inti menonjol besar - EMA
- Sitoplasma lebar, translusen, - CEA
vakuola, musin
- CK 7
- TTF1
- NAPSIN
Adenokarsinoma
micropapillary Lapidic

Solid

mucinous Acinar
 Morphology aspect - Adenocarcinoma
Cytomorphology of
Adenocarcinoma
• FNA smear are usually cellular
• Honeycomb-like sheets, three
dimensional, acini, papillae/glandular
formation
• Eccentrically placed, round or
irregular nuclei
• Finely textured chromatin
• Large nucleoli
• Mucin vacuoles
• Translucent, foamy cytoplasm

Pulmonary cytopathology. Erozan YS et al, Springer 2009.

 Bronchioloalveolar carcinoma
WHO 2004

Syed Z. Ali, Grace C. H. Yang, eds. Lung and mediastinum cytohistology.

Cambridge University Press 2012
https://www.ncbi.nlm
.nih.gov/pmc/articles/
PMC4272758/figure/
F1/
https://www.ncbi.nlm
.nih.gov/pmc/articles/
PMC4272758/figure/
F1/
NEUROENDOCRINE TUMOR
 NEUROENDOCRINE TUMOR

WHO 2004
 Cytology features of pulmonary
neuroendocrine Tumor

Cibas ES. Cytology. Diagnosis principles and Clinical correlate

tipik atipik
 Karsinoma Sel Kecil (Neuoendocrine
Carcinoma)
• SITOLOGI • IMUNOHISTO
- streaks/baluran sel - CD 56
- sebaran sel ireguler,sinsitial, berderet - chromogranin
- N/C rasio tinggi - synaptophysin
- nuclear moulding’
- inti ovoid, ireguler
- kromatin ‘salt and pepper’
- mitosis
Histologi
 Cytomorphology
•Small cells ( 2-3 x size of
lymphocyte)
•Carrot shape nuclei
•Evenly dispersed , powdery chromatin
•Nuclear molding
•Small to indistinct nucleoli
•Paranuclear blue bodies
•Mitoses
•Scant cytoplasm
•Background of nuclear debris and
crush artifact
•High mitoses/karyorrhexis
Karsinoma Sel Kecil
 Karsinoma Sel Besar
SITOLOGI IMUNOHISTO
✓ gambaran tidak spesifik ✓ Petanda
neuroendokrin
✓ sel bergerombol atau tersebar
✓ batas selular tidak jelas, ✓ seperti NSCLC
✓ kolompokan tidak teratur
✓ inti bulat sp tak teratur,kromatin tdk
teratur
✓ anak inti sangat menonjol
✓ sitoplasma sedikit dan basofilik
LARGE CELL CARCINOMA LARGE CELL NEUROENDOCRINE
CARCINOMA
Karsinoma Sel Besar
 A B

LARGE CELL CARCINOMA.

A. Bronchial washing B. Transthoracic FNA. The cells with pleomorphic nuclei with
focal parachromatin clearing and multiple irregular nucleoli/ macronucleoli
Pulmonary cytopathology. Erozan YS et al, Springer 2009.
Metastastic Tumors
The lung is the most common site of
metastatic neoplasms

Spread to the lungs via the blood or lymphatics

or by direct continuity.

>> esophageal carcinomas and mediastinal

lymphomas
 Pleura < 15 mL of serous, relatively acellular, clear fluid lubricates the
pleural surface

Inflammatory Pleural Effusions Non Inflammatory Pleural Effusions

+ Serous, serofibrinous, and fibrinous
pleuritis
+ Penybb pleuritis → tuberculosis,
pneumonia, lung infarcts, lung
abscess, and bronchiectasis
+ A purulent pleural exudate
(empyema) → bacterial or mycotic
seeding
+ Hemorrhagic pleuritis: sanguineous
inflammatory exudates →
hemorrhagic diatheses, rickettsial
diseases, and neoplastic
involvement of the pleural cavity
+ serous fluid within the pleural cavities:
hydrothorax → >>cardiac failure
+ The escape of blood into the pleural
cavity: hemothorax → Kompl ruptur
aneurisma aorta, vascular trauma,
post op
+ Chylothorax : an accumulation of milky
fluid, usually of lymphatic origin → >>
obst atau trauma duct thoraksikus
atau rupture duct limfatikus utama
Pleural Tumors
Solitary Fibrous Tumor

A soft-tissue tumor with a propensity to occur

in the pleura and, less commonly, in the lung,
as well as other sites
Small (1 to 2 cm in diameter)

Tumor shows whorls of reticulin and collagen

fibers among which are interspersed spindle
cells resembling fibroblasts;

IHC: CD 34 (+); keratin (-)

Jarang menjadi malignan

Tidak berhubungan dgn paparan asbes

 Malignant Mesothelioma

Berhubungan kuat dg paparan

asbes

Epithelioid (60%), sarcomatoid

(20%), or mixed (20%)

Epithelioid type : cuboidal,

columnar, or flattened cells
forming tubular or papillary
structures resembling adenoca;
(+) prot keratin, calretinin

Sarcomatoid type : a spindle cell sarcoma,

resembling fibrosarcoma

Mixed (biphasic) type : contains both epithelioid

and sarcomatoid patterns
 Faktor yang berpengaruh pada
diagnosis keganasan paru
• Sitologi: sputum; bilasan dan
• Ketrampilan klinisi
sikat bronkhus; TBNA; TTNA;
mendapatkan bahan
BAL
pemeriksaan
• Histopatologi: TBLB; biopsi core;
• Ketrampilan dan biopsi insisi; biopsi eksisi; operasi
pengalaman SpPA • Diagnostik: sitologi; histopatologi;
imunohistokimia; molekuler
 LUNG CYTOLOGY - SENSITIVITY
◼ Sampling :
❖ Sputum : 27 – 41%
❖ Bronchial brushing : 70-77%
❖ Bronchial washing :61-76%
❖ BAL : 37,5%
❖ FNA : 75 –95%
❖ The overall diagnostic accuracy of cytology :
sensitivity 87% and specificity 90%
◼ Localization of the tumor
◼ Experience of cytopathologist
MODALITAS PEMERIKSAAN
PATOLOGI ANATOMI
Collecting sputum
◼ Sputum early morning
◼ No dental-brushing
◼ Deep cough, can be induced
◼ Collect in a clean tray
◼ Send to PathLab as soon as possible/ fix into alcohol 75%
or put into saccomano solution
 Bronchoscopy: Brushing
A small brush can be
used to collect cells
from the airways

www.tobacco-facts.info/images/brush-bronchosc
Prof. R. Huber, Zurich, 25.11.2009 Confidential – For Internal Use Only 37
 Transbronchial Needle Aspiration

Cells from extrabronchial lymph nodes or tumour can be

collected using fine needle aspiration

http://www.immersion.com/images/global/markets/medical/endoscopy/EN-tbna-corina-02.jpg
Prof. R. Huber, Zurich, 25.11.2009 Confidential – For Internal Use Only 38
 Central Tumours

For central tumours the individual

bronchoscopic techniques provide a diagnosis
in most patients (68–80%)

Prof. R. Huber, Zurich, 39

Biopsies are the most common and preferred tissue acquisition method

Open biopsy Bronchoscopic biopsy

If surgery is recommended Within the different forms
during early-stage NSCLC, of biopsy currently
a tumour tissue sample can employed, biopsy via
be obtained. One example bronchoscopy forceps is
of this is video-assisted the preferred method
thoracic surgery (VATS)

VATS Core needle biopsy

Small or large tissue Biopsy samples can be
samples can be taken obtained using a needle
from the edges of the which is inserted into a
tumour. A camera and very small incision
forceps are guided to the
tumour through an incision
Before biopsy: X-ray and/or CT scan helps to select the most appropriateapproach
During biopsy: Imaging techniques (CT, Fluoroscopy or EBUS) may be used to guide biopsy
 Fine-needle Aspiration

Prof. R. Huber, Zurich, 25.11.2009 Confidential – For Internal Use Only 41

 Histologic type Sputum/Bronchoscopy FNA
cytology material

Squamous Cell 85% 80%

Carcinoma
Adenocarcinoma 79% 96%
Large Cell Carcinoma 30% 42%
Small Cell Carcinoma 93% 92%
 MOLECULAR TESTING IN NSCLC: EGFR
• Diagnosis
– EGFR status correlative with tumor type
– Present in adenocarcinoma and adenosquamous carcinoma
– Rare in large cell and squamous cell carcinomas
– Absent in mucinous BAC, invasive mucin producing
adenocarcinoma (KRAS mutation)
• Prognosis
– EGFR status correlative with aggressive biologic behavior
• Predictive
– EGFR status correlative with tumor response to EGFR
tyrosine kinase inhibitor (TKI) based therapy
Driver mutations in NSCLC patients with ADC histology

No Mutation

KRAS
AKT1

NRAS
ALK EGFR
ALK
MEK1
MET AMP

HER2 DOUBLE
PIK3CA MUTANTS
DOUBLE
BRAF MUTANTS
Thoracic surgery, radiation therapy,
and chemotherapy:
o overall 5-year survival rate is only 16%.
o The 5-year survival rate is 52% → still
localized,
o 22% → regional metastasis
o only 4% with distant metastases
o Small cell ca → 1 year survival
Targeted therapy:
o EGFR (present in about 15% of all
patients)
o or in other tyrosine kinases with specific
inhibitors of the mutated kinases
o Me ↑ survival
o Mutasi K-RAS → prognosis > buruk
 Chemo-regimen and targeted therapeutic
response in NSCLC

• Gemcitabine and doxetacel has higher response in adenocarcinomas

• Cisplatinum and doxetacel has higher response in non-
adenocarcinoma
• Targeted therapy against EGFR (gefitinib /erlotinib/cetuximab) has
higher response in adenocarcinomas
• Pemetrexed in combination with cisplatin is used for first-line
treatment of advanced or metastatic nonsquamous NSCLC
 Clinical reasons to distinguish cases of
adenocarcinoma from squamous cell carcinoma
• Advanced lung ADC or unsp NSCLC with +ve for EGFR mutation are
more likely to respond to treatment with tyrosine kinase inhibitor
• ADC or unsp NSCLC have good respond to pemetrexed than SqCC
• Bevacizumab is contraindicated in patients with SqCC

*Travis 2011
 Dr. Manuel Salto-Tellez, LMS FRCPath (2010)

MACRO HISTO IHC IN SITU HYBRIDIZATIONS PCR

SINGLE DIAGNOSTIC OPINION

PROVIDED BY THOSE WHO CAN COMBINED THE

TRADITIONAL AND THE MOLECULAR PATHOLOGY
KNOWLEDGE OF THE DISEASE

Modern pathology must be a synergy of morphology, IHC and molecular Dx

HOT ISSUE................................
IMUNOTERAPI→ PD1 - PDL1
Sistem penamaan diagnosis→ based molecular
types→terapi
NUT carcinoma
SMARCB1 deficient sinonasal carcinoma
Adeno ca→ diferensiasi kelenjar
atau prod. musin; Squamous cell ca→ Men >>;
asinar, lepidic, papillary, smoking>>;
micropapillary, solid dg prod keratinisasi vs poorly diff;
musin; Umumnya sentral
Perifer Marker: P63, P40
Marker: TTF-1, napsin A
Small cell ca→ >> merokok
arise in major bronchi/periphery;
Large cell ca→ undiff tumor epitel;
no preinvasif >> agresif; high grade no squamous or gland diff
Sitoplasma sedikit,batas tidak jelas, finely
granular nuclear chromatin (salt and large nuclei, prominent nucleoli, a
pepper pattern), absent or inconspicuous moderate amount of cytoplasm;
nucleoli; mitotic >> Hist variant; large cell neuroendokrin
Marker: chromogranin, synaptophysin,
CD57