Welcome !

B.1 session 1
Teaching Assistant 2014
Marcell – Ketip – Romi – Aga – Cisco – Juan – A. Irfan – Audric – Della – Dinda
Marsa – Salli – Yessika - Nugira
 Our Topics

Lung Cancer : Squamous Cell

01 Lymphangioma 03 Carcinoma of Lung

Lung Cancer : Bronchioalveolar

02 Thrombus 04 Carcinoma

Anatomical Pathology | Teaching Assistant 2014

Session Principle
Morphology
Macroscopic & Microscopic

Pathogenesis
Pathophysiology? Diagnostic Approach
Laboratories finding, Radiology etc
Pathology?

Clinical Manifestation Treatment & Staging

Sign & Symptoms

Prognosis Epidemiology
Likely course of a disease
Incidence & prevalence.
Gender/age

Other Names
A disease can have various names

Anatomical Pathology | Teaching Assistant 2014

Lymphangioma

Anatomical Pathology | Teaching Assistant 2014

 Lymphangioma

Definition 01

Lymphangioma are benign, rare, hamartomatous,

congenital malformations arise from lymphatic
vessel endothelium that involve the skin and 02 Analogue with hemangioma
subcutaneous tissues.

Present at birth or during

first year of life 03
 Epidemiology
01 03
account for 4% of all
vascular tumors and Equal sex incidences
approximately 25% of all
benign vascular tumors
in children (US)

No racial predominance
become evident at
any age

02
04
 Embryogenesis,
Blockage or arrest of normal lymphatic tissue lays
growth of the primitive
lymph channels occurs
in the wrong area
during embryogenesis

03
01
Primitive lymphatic
sac does not reach the
venous system
Vascular endothelial
growth ( VEGF )-C and
02 VEGF receptor 3
activation

There are theories explaining about the origin of abnormality

04
Pathogenesis
 lymphangioma
Classification
Simple or capillary
lymphangioma
Simple lymphangioma
Slighly elevated or pedunculated lesion up
to 1-2 cm in diameter.
Predilection : head neck and axilary
subcutaneus tissue
Cavernous lymphangioma or
cystic hygroma
the size of lymphangioma can be large up to
15cm
predilection : neck axilla in children, and more
rarely in the retroperitoneum
Vs
composed of massively dilated lymphatic space
lined by endothelial cells and separated by
connective tissue containing lymphoid agregrate
-un encapsulated

Anatomical Pathology | Teaching Assistant 2014

 Lymphangioma
Classification
according to the size of
the cysts

Microcystic Mixed Macrocystic

composed of cysts, each of contain both microcystic and contain cysts measuring more
which measures less than 2 macrocystic components than 2 cm3 in volume.
cm3 in volume
 Classification
based on
the depth and the size

• Superficial : lymphangioma • Deep-seated group include : cavernous

circumscriptum lymphangioma or cystic hygroma.

Teaching Assistant 2014

Lymphangioma circumsriptum
 Capillary Lymphangioma

Analogue with Capillary Predilection area Usually occurs in skin

Hemangioma head, neck, and axillary
subcutaneous tissues

Anatomical pathology | Teaching Assistant 2014

MACROSCOPIC

• Elevated or sometimes pedunculated lesions up to 1

to 2 cm in diameter
• Soft, cystic, well demarcated
 MICROSCOPIC

Composed of networks of endothelium-lined spaces

The lumina may be either empty or contain proteinaceous fluid and

lymphocytes
 Turner Syndrome
Cavernous Lymphangioma of the neck is
usually associated with Turner
Syndrome

ma
a lo gu e e man
g io
An us h
rno
h ca ve
Wit
Usual
soft ti ly occurs
ssues. in d e e
p
Cavernous
Lymphangioma
Pr
ed
ile
ct

ne per min ry a eu
io

ck tr al nd m
up do nte iton
n

, a u n si t
ab ese per
A

xil k, es
m tro
re

la, lim i n
re
a

gr b clu
oi s a d
n , n in
or d g
al
ca
vi t
y,
 Macroscopic

painless swellings

There is multicystic or spongy mass and also the cavities of which contain
watery to milky fluid

The tumor margins are indistinct and unencapsulated

 MICROSCOPIC

01 02 03
 Characterized by thin-walled, dilated  The lumina may be either empty or  Stromal mast cells are common and
lymphatic vessels of different size, contain proteinaceous fluid and haemosiderin deposition is frequently
which are lined by a flattened lymphocytes seen
endothelium and frequently
surrounded by lymphocytic aggregates
Microscopic appearance of capillary lymphangioma
Cavernous Lymphangioma
Lymphangioma Circumscripta
 Diagnosis
Ph y
sica
l Ex a
m

01
MR Degree of lesion and location
Imm I
un o
hist
oc h 02 FVIII-rAg, CD31 and CD34, D240
emi
stry
(IH
C )
03 Color and microstructure of epidermis in vivo
De r
mo s
cop
Fin ic
ding
s 04
Mini Quiz : What’s this?
 Complication Treatment Prognosis
• Respiratory Obstruction Surgical excision (most recommended) • Lymphangioma practically never becomes
• Infection malignant and is curable by excision

• Ulceration • If there is recurrence, it may be due to

incomplete surgical removal
Thrombus
Anatomical Pathology | Teaching Assistant 2014
 Hemostasis
a series of regulated processes that maintain blood in fluid, clot-free state in
normal vessels while rapidly forming a localized hemostatic plug at the site of vascular injury
NORMAL HISTOLOGY OF ARTERIAL AND VEIN
 Vascular Injury

Vasoconstriction

Normal
Primary Hemostasis
Hemostasis

Secondary Hemostasis

Tertiary Hemostasis
Thrombosis
Thrombus
Pathologic
Pathologic condition
condition of of hemostasis
hemostasis when
when
blood
blood is
is not
not in
in fluid
fluid state,
state, blood
blood clot
clot
formation
formation
final
final product
product of
of coagulation
coagulation process
process in
in hemostasis.
hemostasis.

thrombus
thrombus could
could be
be ::

1 hemostatic clot
Normal

2 the case of thrombosis

Pathological
 3 Regulator of Hemostasis

Coagulation Cascade

Platelets

Vascular Wall
 Pathologic Condition :
Virchow Triad

Endothelial Injury Hipercoagulability

Thrombosis

Abnormal Blood Flow

 01 04
02
Arterial Thrombi 03 Venous thrombi
Type of thrombi

On artery
Mural Thrombi
On Veins
Vegetation
In heart chamber/aorta
On heart valves
 Almost invariably occlusive  Frequently Occlusive
 Red/Stasis thrombi  White thrombi


Mainly erythrocyte
At site of stasis
Thrombi  Mainly platelet or fibrin
 At site of turbulence/endothelial injury
 Extends in the direction of blood  Grows retrograde


flow
Deep vein thrombosis (DVT),
Venous Vs Arterial  Myocardial infarction, unstable angina,
ischemic stroke
pulmonary embolism
Fate of Thrombus
Macroscopic
 Microscopic feature
• An abnormal dilation of blood vessels with
smooth muscle hypertrophy and subintima
fibrosis.
• Edematous stroma has infiltrates of chronic
inflammatory cell infiltration
Thrombus of Coronary Artery
What Phase is this?
Quiz : What Phase?
Lines of zahn
 Treatment
Anticoagulant
For both arterial and venous.

Antiplatelet
Especially for arterial, because arterial
thrombi consists of platelet.
Overview :
Lung
Anatomical Pathology | Teaching Assistant 2014
ANATOMY
Bronchiole
 Terminal
Bronchiole
Alveolus
Epidemiolog • Most common cancer in the world.

y •
•
•
Men vs women = 1.5 : 1
Age over 40 y.o
Squamous cell carcinomas (Men >
Women)
• Adenocarcinomas (Men < Women).

Risk
factors
 Signs and symptoms?
Paraneoplastic Syndrome?
Lung cancer
 Lung Cancer Classification by Histology
NSCLC-NOS
~25%
• Can occur in any part of the lung
Large cell
~10%
Nonsquamous

• Adenocarcinomas are often found in an outer area of

Adenocarcinoma
NSCLC ~40%
the lung
85%-90% • Most common subtype in nonsmokers

Squamous and • Squamous cell carcinomas are usually found in the

Squamous transitional cell center of the lung, next to an air tube (bronchus)
25%-30% • Almost all cases are in smokers

SCLC • Often start in the bronchi near the center of the chest
10%-15% • Tend to grow and spread quickly

SCLC, small cell lung cancer.

American Cancer Society. http://www.cancer.org/cancer/lungcancernonsmallcell/detailedguide/
nonsmallcelllungcancerwhatisnonsmallcelllungcancer. Accessed August 19, 2015.
Lung cancer
 Small cell lung
• Synonym: oat cell carcinoma cancer (20%)
• Neuroendocrine tumor
• IHC: synaptophysin, chromogranin, neuron-specific enolase
(NSE)
 Non-small cell lung cancer (80%)

NSCLC is any type of epithelial lung cancer other than small cell
lung cancer. Non-small cell lung Ca usually grows and spreads
more slowly than SCLC

• Squamous cell carcinoma (25-30%) usually arise centrally in

larger bronchi
• Adenocarcinoma (30-35%) are often found in the periphery
of the lungs
• Large cell carcinomas (10-15%)
Diagnostic Tests
• CXR
• CT Scans
• MRI
• Sputum cytology
• Fibreoptic bronchoscopy
• Transthoracic fine needle
aspiration
• Transthoracic Biopsy
• Thoracocentesis
SCC of L ung
n o c e ll u la r C a r c in oma
• P la
o c e ll u la r C a r c in o m a
• Squam
ma
• E p i d e r m o id C a r c in o
a m o u s C e ll E p i th e li o m a
• Squ
SCC of Lung
Definition Epidemiology Site of Involvement

Malignant epithelial tumor The majority of squamous

Over 80% of squamous cell lung carcinomas arise
showing cell lung carcinomas
Keratinization and/or centrally in the
occur in smokers
Intercellular cigarette smokers primary, lobar, or
Bridges that arises from segmental
bronchial bronchus.
Pathogenesis
GOBLET CELL BASAL CELL SQUAMOUS
HYPERPLASIA HYPERPLASIA METAPLASIA

SCC CARCINOMA IN SITU SQUAMOUS DYSPLASIA

 Molecular Pathogenesis
Smoking -> Chromosomal aberration, especially deletion
on tumor suppressor loci :

a. 3p, 9p (CDKN2A gene)

b. 17p (TP53 gene)
MACROSCOPIC
 RE M
MICROSCOPIC Interce EMBER!
llular
K e r at bridg
i ng
• SCC of the Lung shows   inizat
Patho ion
These features vary with degree of logica
(I,K,M l Mit
differentiation ) o s is

Differentiation Well Moderate Poor

Keratinization Keratin pearl Individualized absent

Intercellular
present present absent
bridging
Do you agree it’s SC
C of lung? What degr
ee?
 Diagnosis
• IHC
- Positive: P63, CK 5/6, EMA, CEA
- Negative: Vimentin, TTF-1, Napsin A
• Imaging: Chest X Ray, PET Scan, CT scan, MRI.
• Bronchoscopy
• Sample collection: thoracocentesis,
transthoracal biopsy, sputum cytology
ST
AG
IN
G
 • Irregular hyperchromatic nuclei
CYTOLOGY • Bizarre cells: spindle-shaped and tadpole-
shaped cells
• Keratinized Cytoplasm
Treatment
● Surgery
● Chemotherapy
● Radiotherapy
Bronchioalvelor Carcinoma
 Definition Epidemiology Site of Involvement
Malignant epithelial tumour with The most common lung cancer in Arise peripherally
glandular differentiation or non-smoker woman
mucin production.
Pancoast Tumor
Located at the Lung Apex

Compress the following structures:

V. Brachiocephalic
A Subclavian
N. Phrenicus
Brachial plexus
N. Recurrent laryngeal  hoarseness
N. Vagus
Sympathetic trunk  Horner's Syndrome.
PAMELA (Ptosis, Anhidrosis, Miosis, Endophtalmus,
Loss of ciliospinal reflex)
 Precursor Lesion
Atypical Adenomatous Hyperplasia (AAH)  Non Mucinous BAC.
 AAH
|
Atypical
Adenomatous
Hyperplasia
Pathogenesis • Gain-of-function mutations in multiple genes
encoding receptor tyrosine kinases, including
EGFR, ALK, ROS, MET, and RET, which are all
also mutated in other forms of cancer
• Tumors without tyrosine kinase gene mutations
often have mutations in the KRAS gene, which
you will remember lies downstream of receptor
tyrosine kinases
MACROSCOPIC

• Single or Multiple Nodule

• Nodule  solid, gray-white
area with mucus
• Gray white central fibrosis
 01
Microscopic Grows along pre-existing structure without
destructing the alveolar structure.

Lepidic Pattern 02
resembling butterflies sitting on a fence

03
No stromal, vascular, or
pleural invasion

Septal widening with 04

sclerosis is common
(particularly non-mucinous
variant)
 • Columnar, peg-shaped, or cuboidal
cells
• Shows :
• Clara cell  columnar, may be apical
nuclei)
• and/or type II (cuboid or dome-shaped)
cell differentiation
• Degree of nuclear atypia and nucleolar
prominence is GREATER
• Most solitary BAC
NON
MUCINOUS
TYPE
 MUCINOUS
• Low grade, tall columnar cells with
basal nuclei and pale cytoplasm TYPE
(sometimes resembling goblet cells)
• Cytoplasmic and intra-alveolar
mucin
• Can spread aerogenously and form
satelite tumor
• Extensive consolidation is common,
with a lobar and/ or pneumonic
pattern
 CYTOLOGY
• Arranged in three-dimensional
morulae, pseudopapillae, true
papillae or/and sheets of cells.
• In most cells the cytoplasm is
distinctly homogeneous or
granular and in others is
foamy due to abundant small
indistinct vacuoles.
 • Transthoracic Needle Aspiration
• Transthoracal biopsy
• Effusion fluid cytology

DIAGNOSIS •
•
Imaging : CT, chest X-ray
Molecular Diagnosis: EGFR, ALK, KRAS

What is
Protoncogene?

How about tumor

suppressor gene?
Molecular diagnosis
• EGFR (Epidermal Growth Factor Receptor)
• KRAS (Kirsten Rat Sarcoma)
*EGFR and KRAS  PCR Amplification & Dye
Terminator Sequencing
• ALK (Anaplastic Lymphoma Kinase)  FISH
(Fluorescence in-situ hybridization)
 RAS-RAF-MEK-ERK SIGNALING PATHWAY

• Mutation in EGFR  constitutive activation of EGFR

• Mutation in KRAS (G-protein)  constitutive activation of signaling pathway
downstream of EGFR
Activating EGFR mutations confer a greater sensitivity to EGFR TKIs

Chromosome 7 EGFR gene

The majority of EGFR

tyrosine-kinase domain
mutations In NSCLC are
Exons 1–16 activating mutations (exon

EGFR
Extracellular
domain 85% 19 deletions and the exon 21
L858R mutation)

Exon 17
Transmembrane
domain

Exons 18–24
Tyrosine-kinase
domain

Exons 25–28 The clinical efficacy of EGFR TKIs, such as

Regulatory erlotinib, has been established in the most
domain
common EGFR mutations

Exon 19 deletions and the L858R mutation confer sensitivity to EGFR TKIs
× EGFR Mutation  Treatment
× T790M Mutation
 BAC (Non BAC
Metastatic Immunohistochemistry
||
IHC colorectal
mucinous) (mucinous)
adenocarcinoma

CK7 + + - IHC
CK20 - + +
TTF-1 + - -  PE-10  detect surfactant
CDX2 - - + apoprotein in BAC
 EGFR  for therapy determination

 Mucinous Tumor BAC :

TTF-1 (-)

 CK-7 and CK-20 (+)

 Metastasis
& Staging

Grow slowly but Primarily spreads via Brain, bone, adrenal staged according to
Metastasize early Aerogenous route  glands and liver are the the International
Hematogenous and
Lymphatic routes mucinous type most common TNM System.
metastatic sites
Add an image

Treatment

Surgery Chemotherapy or Targeted Therapy

Radiotherapy
 MoAb that inhibit EGFR 
Lower Grade tumors are
Cetuximab, panitumumab
more Resistant to  Inhibit EGFR  Erlotinib, gefitinib
chemotherapy.  Inhibit ALK  Crizotinib
 Prognosis
Solitary lesion  Excisable  5-
year survival rate 50-75%.

Generally  the 5 year survival rate 25%.

tumor size of 2.5 cm or more, micropapillary and

solid variants as predictors of poor prognosis

2015 WHO Classification of Lung Tumor

Thank You