ANATOMI PATOLOGI

BLOCK 3.6
 TOPIC
1. NASAL POLYP

2. INVERTED PAPILLOMA

3. BRONCHIOLOALVEOLAR CARCINOMA OF THE LUNG

4. SQUAMOUS CELL CARCINOMA OF THE LARYNX

Nasal Polyp
 “ Nasal polyps are soft, painless,
What is it??? noncancerous growths on the lining of
nasal passage or sinuses .”

Adults 1-4%
Children 0.1%
Epidemiology?
Male : Female  2-4 : 1
Increasing incidence with age

 chronic inflammation (ex : asthma)

 recurring infection
Etiology?  allergies
 drug sensitivity
 certain immune disorders
ETIOLOGY
 Chronic rhinosinusitis (3-4 length)
 Samster’s triad
 Cystic Fibrosis (polyp in children)
 Young’s Syndrome
 Churg-Strauss Disease
PATHOPHYSIOLOGY

• 20-50% have asthma (Ig E

mediated imune reaction-
hypersentivity type I)
• 8-25% have aspirin intolerance
Allergic • 50% have alcohol intolerance
• Characteristic : edema, redness,
and mucous secretion, with
lymphocytic infiltration
(eosinophil dominant)
 • Cystic fibrosis (6-48% polyp in young age)
• Samster’s Triad (nasal polyposis, asthma
and ASA intolerance)
• Young’s Syndrome

Non • Churg Strauss Disease (34%)

• Infectious rhinitis : adenovirus,
Allergic echovirus, rhinovirus
• Characteristic of infections : nasal
mucosa  thickened, edema, red; nasal
cavity  narrowed, and turbinates are
enlarged. Sometimes exudate 
suppurative or mucopurulent.
CLINICAL PRESENTATION
 Asymptomatic
 Airway Obstruction
 Postnasal drip
 Dull headache
 Snorring
 Rhinorhea
 Hyposmia/Anosmia
 Epistaxis
 Obstructive Sleep Apnea
 Craniofacial abnormalities
 Optic nerve compression
MACROSCOPIS
 Focal protrusions of
mucosa, which may
reach 3-4 cm in
length.
 Pale smooth,
shinning and
edematous mass
 Soft when compared
to surrounding
mucosa
 Presence of surface
ulceration suspect
bacterial inf.
 Bilateral
 OTHERS??
 Choanal Polyp  polyp arising from one paranasal
sinuses

antrochoanal sphenochoanal ethmoidochoanal

 MICROSCOPIC
 Epithel  pseudostratified collumnar ciliated
(respiratory mucosa) Thickened basal membrane
 Loose mucoid and edematous stroma
 Infiltration of inflamatory cells *(predominant
eosinophil)
 Hyperplasia and dilatation of sero-mucin gland *(may
exhibit foci of squamos epithelium)
Epithelium pseudostratificatum
columnar with cilia

m. basalis

Stroma edema
Dilated glandula with sero
mucin
Edema stroma
Goblet cell

Infiltration of
inflammatory cells

Blood vessel
Charcot-Leyden Crystal
HELLQUIST CLASSIFICATION
 Type 1: edematous eosinophilic polyps
(morphologic characteristics: edema, goblet cell
hyperplasia, thickening of the basement membrane,
predominantly eosinophils)
 Type 2: Fibroinflamatoric neutrophilic polyps
(morphologic characteristics: chronic inflammation,
predominantly neutrophils, epithelial metaplasia)
 Type 3: Seromucinous gland hyperplasia
 Type 4: Polyp with atypical stroma
 •Steroid nose drop (betamethasone, fluticasone)
•Steroid tablets (prednisolone)
•Polypectomy, endoscopic sinus surgery
Treatment •Others: decongestant (xylomethazoline (Otrivine) (do not
use >10 days), saline nasal douches
•Prevent recurrence: steroid nasal spray (budesonide,
fluticasone, beclometasone, triamcinolone, mometasone

• Rarely transform into neoplastic

Prognosis • Often locally recurrent, due to
unknown persistent pathogenesis
 Of the nasal cavity
Also called : schneiderian
 “Benign neoplasma from respiratory
What is it??? mucosa arise from squamous or
columnar epithelial.”

1-5% of sinonasal tumors

Epidemiology? Commonly in men with the main complaints
are nasal stuffness, nasal obstruction, and
epitaxis.

Etiology? HPV type 6 and 11 infection

Clinical Presentation
Nasal stuffness, nasal obstruction, and epitaxis, and rhinorrhea
Rarely invasion to CNS
Commonly UNILATERAL
Subtypes are :
inverted (47-78%)
fungiform (6-50%)
 oncocytic (2-26%)
Variant cell tumor : cylindris or squamous or transtitional
From location :
Nasal septum tumor : Exophytic and mushroom shaped
 Lateral wall (middle meatus) : Inverted type
Oncocytic Also called “cylindrical cell or columnar
cell papilloma”
HPV –
Microscopic :
Endophytic or exophytic
Irregularly distributed tall columnar
cells, 2-8 layers thick, with finely
granular eosinophilic cytoplasm
resembling oncocytes
Nuclei are small, dark and uniform or
slightly vesicular
Indistinct nucleoli
Intraepithelial mucin filled cysts with
neutrophils
Edematous to fibrous stroma
Variable inflammatory infiltrate, but
few eosinophils
No/rare minor salivary glands
Fungiform Exophytic connective tissue stalks,
often with serpiginous
configuration, with delicate
fibrovascular cores, lined by
benign squamous or intermediate
epithelium
May contain respiratory,
intermediate or mucus secreting
cells
Variable koilocytosis and residual
goblet cells
Usually no/scant surface
keratinization
No/rare mitotic figures, minimal
inflammatory cells
Inverted

The one we are going to talk

about.........
MACROSCOPIC
Pink-tan-gray
Soft to
moderately firm,
Polypoid growth
with convoluted
or wrinkled
surface
MICROSCOPIC
Hyperplastic epithelium, 5-30 cells thick, enclosed by basement
membrane, which grows endophytically into underlying stroma
Epithelium is squamous or respiratory-type mixed with goblet cells
(***May have transitional-type epithelium)
10-20% have focal surface keratinization
5-20% display dysplasia
No/few mitotic figures
Variable stroma (dense/fibrous or loose/myxoid), variable
inflammatory cells but usually no eosinophils
Usually no/few minor salivary glands
Often coexists with ordinary nasal polyps
 Edematous stroma
Infiltration
inflammatory cell

m. Basalis stili
intact
Pseudostratificatum
columnar
Metaplasia squamous
Metaplasia squamous
Treatment

Excision
Lateral rhinotomy and medial
maxillectomy with
meticulous removal of all
mucosa in ipsilateral
paranasal sinuses
With this approach, 0-30%
recurrence rate
Can remove endoscopically if
very small
Prognosis

3% develop carcinoma after excision, which has

only a 25% survival rate
3% (particularly inverted and oncocytic subtypes)
have coexisting focal invasive carcinoma, which
has an excellent prognosis
About 96% of the patients are males
Most patients are >50 years old, but cases in
much younger patients are on record
95% of laryngeal carcinomas are squamous
cell carcinoma
 Smoking
Alcohol
HPV infections (HPV-16 &
HPV-18)
Non smoker young patients
Nutritional factors
Exposure to asbestos
Irradiation
 Persistent
hoarseness
Pain
Dysphagia
Hemoptysis
Vulnerable to secondary
infection due to the
ulcerating lesion
1. Glottic (60-65%)
– Arise from true vocal cords
– Tend to remain localized for long periods because of
the surrounding cartilaginous wall and the small
number of lymphatic vessels
– Most are well to moderately differentiated
– Prophylactic lymph node dissection is NOT INDICATED
– Treatments: irradiation therapy, endoscopic removal
of true cord (cordectomy), hemilaryngectomy (if T2)
2. Supraglottic (30-35%)
– Involves the false cord, the
ventricle, and/or the laryngeal
or lingual surface of the
epiglottis
– 40% has lymph node
metastases; 20-35% is occult
lymph node metastases on
microscopic examination
– Treatments: irradiation or
laryngectomy
3. Transglottic (<5%)
– Are cancers that
cross the laryngeal
ventricle
– Highest incidence
of lymph node
involvement (52%);
31% had clinically
undetected node
metastases
– Treatment: total
laryngectomy +
elective lymph
node dissection
4. Infraglottic/subglottic (<5%)
– Cancers of true cord extending to
subglottic of more than 1 cm OR
tumors entirely limited to the
subglottic area only (very unusual)
– Destruction of interthyrocricoid
membrane  invasion of the
prelaryngeal wall and thyroid
gland
– Frequent extension to the trachea
– Most are moderately to poorly
differentiated
– Radical node dissection with
clearance of paratracheal nodes is
indicated
 Epithelial changes vary from smooth, white or
reddened focal thickenings (sometimes roughened
by keratosis) to irregular verrucous or ulcerated
white-pink lesions that are similar in appearance to
carcinoma
They begin as in situ lesions that later appear as
pearly gray, wrinkled plaques on the mucosal
surface, ultimately ulcerating and fungating
Squamous differentiation, often seen as keratinization with
variable “pearl” formation, and invasive growth are the
features of SCC
Stromal reaction: desmoplasia, myofibroblasts
proliferation, and neovascularization
Grading:
• Well differentiated
• Moderately differentiated
• Poorly differentiated
• Based on the degree of differentiation, cellular pleomorphism,
and mitotic activity
• REMEMBER: Intercellular bridging, Keratinization, Mitosis
pathologis
 CD34 (-) & SMA (+)  invasive carcinoma
Cytokeratins
Medium/high molecular weight  Low-grade SCC
Low molecular weight  High-grade SCC
**High-grade SCC may express vimentin
The approximate 5-year survival rates for the
different types are the following:
– Glottic: 80%
– Supraglottic: 65% (with those located in the
aryepiglottic folds having the worst prognosis)
– Transglottic: 50%
– Subglottic: 40%
LUNG CANCER
For clinical use:
Small cell carcinoma
Almost always metastatic but highly
responsive to chemotherapy and/or
radiotherapy
Non small cell carcinoma
Less often metastatic but less responsive to
chemotherapy and/or radiotherapy
 • Lung cancer is the • Tobacco smoking
most frequently • Industrial hazards
diagnosed cancer • Air pollution
and the most
common cause of • Genetics
cancer mortality in • Precursor lesions
the world
• Most often occurs
between ages 40-
70; peak in the 50-
60s

Adenocarcinomas
Most commonly found in lifetime nonsmokers, women, and young
patients (<45 years old). EGFR mutations are commonly found in
bronchioloalveolar carcinoma  useful for targeted therapy.
Bronchioloalveolar Carcinoma
Adenocarcinomas are usually located more
peripherally : alveolar septal cells or
terminal bronchioles
Transthoracic Biopsy (TTB) /
Transthoracic Needle Aspiration /
Percutaneous Needle Aspiration
May occur as a single nodule or, more
often, as multiple diffuse nodules that
sometimes unite to produce a
pneumonia-like consolidation
The nodules may have a mucinous, gray
translucence when secretion present OR
appear as solid, gray-white areas that can
be confused with pneumonia
Tumor cells grow along preexisting
structures without destruction of alveolar
architecture (lepidic pattern: “butterflies
sitting on a fence”)
No stromal infiltration
Nonmucinous (60-75%)
Collumnar, peg-shaped, or cuboidal cells
The degree of nuclear atypia and nucleolar
prominence is GREATER than in the
mucinous variety
Mucinous
Distinctive, tall, columnar cells with
cytoplasmic and intra-alveolar mucin
 PE-10  detect surfactant apoprotein in BAC
 EGFR  for therapy determination
BAC Metastatic colorectal
IHC
(Nonmucinous) adenocarcinoma
CK7 + -
CK20 - +
TTF-1 + -
CDX2 - +
 Is tumor located at the lung apex
 Microscopically may appear as SCC,
adenocarcinoma, large cell, etc. But mostly are
adenocarcinomas.
 It may compress the following structures:
Brachiocephalic vein
Subclavian artery
Phrenic nerve
Brachial plexus
Recurrent laryngeal nerve  hoarseness
Vagus nerve
Sympathetic trunk  Horner's syndrome.
• 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
Exons 1–16 domain mutations In
EGFR
Extracellular
domain 85% NSCLC are activating
mutations (exon 19
deletions and the
Exon 17
Transmembrane exon 21 L858R
domain mutation)

Exons 18–24
Tyrosine-kinase
domain

Exons 25–28 The clinical efficacy of EGFR TKIs,

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

Exon 19 deletions and the L858R mutation confer sensitivity to EGFR TKIs
 Non-small cell lung cancers have also been linked to
rearrangements of the gene encoding ALK.
 Most common ALK rearrangement
fusion between echinoderm microtubule-associated
protein-like 4 (EML4) and ALK gene on chromosome 2p23
 In cell line and mouse models, EML4-ALK is highly
oncogenic, activates the PI3K-AKT and MAPK-ERK
pathways and induces lung tumors
 EML4-ALK most commonly seen in adenocarcinomas of
nonsmoker or light smokers, without EGFR &KRAS
mutations. **Patients tend to be younger than most
patients with non-small cell lung cancer.
 EGFR, KRAS, and ALK mutations are almost always mutually
exclusive -> all three are tested together
 EGFR and KRAS: polymerase chain reaction (PCR) amplification
and dye-terminator sequencing:
 Covering the kinase domain of the EGFR gene (exons 18-
21)
 Covering codons 12 and 13 (exon 1) and codon 61 (exon 2)
of the KRAS gene
 Analytical sensitivity: 10% to 20% tumor cells in the
background of normal cells. Testing is performed on
sample where tumor is enriched.
 ALK: fluorescence in-situ hybridization (FISH) testing
with ALK break-apart probes to detect rearrangements

1. Histopathology Diagnosis

– Morphology:
Adenocarcinoma VS Squamous cell
carcinoma
– IHC
TTF1 +ve P63 +ve
CK 5/6 +ve
 2. IDENTIFYING EGFR STATUS
IHC for EGFRColoured product
Substrate

Enzyme-conjugated
secondary antibody
(specific for primary
antibody)

Primary antibody
(EGFR-specific)

EGFR

Thin tissue section from formalin-fixed,

paraffin-embedded tumour block
EGFR MUTATION TEST
POSITIVE
Immunohistochemistry (IHC)
staining of lung
adenocarcinomas with
epidermal growth factor
receptor (EGFR) mutations.
Representative tumours with
staining intensity from score
0 to 3 + are shown
Positive immunoreactivity is
defined as an IHC score equal
to or greater than 1+.
 EGFR MUTATION POSITIVE ….. TKI
www.thescientist.com
 EGFR mutations influence therapy choice
Common mutations confer sensitivity to TKIs1–6

Activating EGFR mutation present

 Deletions in exon 19
 Point mutation in exon 21
 Point mutations in exon 18

Tumor sensitive to TKIs

Patient is likely to respond

to TKI first-line therapy

1Mok TM et al. N Engl J Med 2009;361:947–957; 2Maemondo M et al. N Engl J Med 2010;362:2382–2388;
3Rosell
R et al. N Engl J Med 2009;361:958–967; 4Lynch TJ et al. N Engl J Med 2004;350:2129–2139;
GARRIDO
5Jackman DM et etal.
al. ClinClin Transl
Cancer Oncol 2012;14:338-49
Res 2009;15:5267–5273; 6Maheswaran S et al. N Engl J Med 2008;359:366–377.
 With chemotherapy
or radiotherapy
 Targeted therapy
aiming at the
epidermal growth
factor receptor
(EGFR)
 Tumor grade is
associated with its
sensitivity to
chemotherapy.
Lower grade tumors
are more resistant to
chemotherapy.
• Cetuximab, panitumumab  MoAb that inhibit EGFR
• Erlotinib, geftinib  small molecule that inhibit EGFR
• Crizotinib  small molecule that inhibit ALK