Rs pathology 02

Respiratory module part 2
Dr.Ghada Al-jussani
MBCHB.,FRCpath (UK)
Iraqi board in Pathology
Jordainan Board in pathology
European Board In Pathology
Assistant Professor
Consultant pathologist
Faculty of medicine ,Hashemite university

Objectives
 Pneumonia Syndromes
 Lung carcinoma
 Pleural lesions
 Nasopharyngeal & Laryngeal carcinoma.

Pulmonary infections
Pneumonia

Pneumonias I
Pulmonary infections in the form of pneumonia is common due to the
following reasons :
1- The epithelial surfaces of the lung are constantly exposed to many
liters of air containing various microbial contaminants .
2- Nasopharyngeal flora are regularly aspirated during sleep , even
by healthy persons .
3- Other common lung diseases render lung parenchyma vulnerable
to virulent organisms .

Pneumonia
Definition : Infection of the lung parenchyma.
May present as acute fulminant clinical disease or as a
chronic disease with a more protracted course .
Acute bacterial pneumonia may present as one of two
anatomic & radiographic patterns :
I- Broncho-pneumonia .
II- Lobar pneumonia

Broncho - pneumonia :
Implies a patchy distribution of inflammation that
generally involves one or more than one lobe .
This pattern results from infection of the bronchi &
bronchioles , with extension into adjacent alveoli .
Lobar pneumonia :
The contiguous airspaces of part or all of a lobe are
homogenously filled with exudate that can be
visualized by radiograph as lobar or segmental
consolidation .

Pneumonia Syndromes
Pneumonias can be classified into seven distinct settings in which
infections & the implicated pathogens are specific to each category .
Including :
I- Community-acquired typical pneumonia .
II- Community acquired atypical pneumonia .
III- Nosocomial ( hospital acquired pneumonia) .
IV- Aspiration pneumonia .
V- Lung abscess ( Necrotizing pneumonia ) .
VI- Chronic pneumonia .
VII-Pneumonia in the immunocompromised patients

Pneumonia Syndromes :
I- Community acquired typical pneumonia :
Most community acquired pneumonias are bacterial infections , not uncommon
this infection follows viral upper respiratory tract infection .
The onset is usually abrupt , with high fever, shaking chills , pleuritic
chest pain & a productive muco-purulant cough , occasional patients
may have haemoptysis .
Streptococcus pneumoniae is the most
common cause of community-acquired acute pneumonia , hence called
pneumococcal pneumonia .
Other bacteria may be involved like , Morexella catarrhalis, Staphyllococcus
aureus , Hemophilus influenzae , Legionella pneumophila & Klebsiella as well as
Pseudomonas sp.

It occurs with increasing frequency in three groups :
(1) Those with underlying chronic lung
diseases such as congestive heart failure(CHF) , chronic obstructive pulmonary
diseases (COPD) , or diabetes .
(2 ) Those with either congenital or acquired
immunoglobulin defects (AIDS ) .
(3) Those with decreased or absent splenic
function ( sickle cell disease or after splenectomy ) This occurs because the
spleen contains the largest collection of phagocytes & is therefore the major
organ responsible for removal of pneumococci from the blood .
As well as it is capable of production of antibodies against encapsulated
bacteria .

Morphology :
In this type of pneumonia both patterns lobar or bronchopneumonia may occur
Bronchopneumonia being more prevalent with advanced age . Regardless to
the pattern , the lower lobes or the right middle lobe are the most frequently
involved.
Before the introduction of antibiotics , the entire lobe is involved by
pneumococcal pneumoniae and evolved into four stages :
Stage of congestion .
Stage of red hepatization .
Stage of gray hepatization .
Stage of resolution .
Early antibiotic therapy alters this typical progression .

Figure 2 : Chest X-ray of patient with pneumonia. The lower lobe is
consolidated (arrow) showing dense homogenous whitish appearance of
pneumonic inflammation of the right lower lobe .

I- Stage of congestion :
During this stage , the affected lobe or lobes are heavy , red & boggy
Histologically : vascular congestion is seen with proteinaceous fluid,
scattered neutrophils & many bacteria in the alveolar spaces .
II- Stage of red hepatization :
Occurs within few days after infection .
The lungs have a red color , liver-like consistency , the alveolar
spaces are packed with bacteria , red blood cells & fibrin with few
neutrophils .

Figure 3 : Microscopic view of the lung in pneumococcal pneumonia ,stage of congestion , showing
congested capillaries in alveolar septa .

Figure 4 : Gross appearance of the lung in pneumonia stage of red hepatization,
the lung is heavy , dark red liver –like consistency .

Figure 5 : Microscopic view of lung in pneumonia , stage of red hepatization , the alveolar spaces
are filled with RBCs & bacteria , fibrin & few neutrophils .

Figure 6 : High power view of lung tissue in pneumonia ,stage arrows). ) ,RBCs seen with bacteria of
red hepatization

III- Stage of gray hepatization :
The lung is dry , gray & firm , with a liver like consistancy because the red cells
are lysed while the fibrino- suppurative exudate persists within the alveoli
.Microscopically: the alveoli are filled with neutrophils & scanty bacteria & RBCs.
IV- Stage of resolution :
Follows uncomplicated cases as the exudates within alveoli are enzymatically
digested to produce granular semi fluid debris that is resorbed or ingested by
macrophages , coughed out or may be organized by fibroblasts growing into it .
The pleural reaction includes fibrinous or fibrino-purulant pleuritis which may
similarly resolve , or undergo organization , leaving fibrous thickening or
permanent adhesions .

Figure 7 : Gross appearance of lobar pneumonia ,showing homogenous gray
consolidation of the entire lower lobe of the lung (stage of gray hepatization ) .

Figure 8 : Microscopic view (high power) of lung tissue in stage of gray hepatization showing
numerous neutrophils (arrows) & macrophages within alveolar spaces ,congested blood vessels
(arrow head ) seen in alveolar septa ..

Figure 9 : Microscopic view of lung tissue in stage of gray hepatization of pneumococcal
pneumonia,the alveolar spaces contain numerous neutrophils with fibrin. Alveolar septa show

Figure 10 : Microscopic view of lung tissue with features of pneumonia showing organization with
fibrous tissue deposition on fibrin in alveolar spaces , occurring in unresolved pneumonia .

In broncho-pneumonia pattern :
The foci of inflammatory consolidation distributed in patches throughout one or
several lobes most frequently bilateral & basal .
Well-developed lesions 3 or 4 cm. in diameter are slightly elevated & are gray –
red to yellow .
Confluence of these foci may occur in severe cases producing the appearance of
lobar consolidation .
The lung substance surrounding the areas of consolidation is usually hyperemic
& edematous , but the larger intervening areas are generally normal
Pleural involvement is less common than in lobar pneumonia .
Histologically : The reaction consists of focal suppurative exudate that
fills the bronchi , bronchioles and the adjacent alveolar spaces .
With appropriate therapy complete restitution of the lung is the rule for both
forms of pneumococcal pneumonia .

Figure 11 : Gross appearance of the lung with broncho-pneumonia ,showing patchy
involvement of lung tissue by whitish areas of inflammation surrounded by red congested
lung tissue .

Figure 12 : Microscopic view of lung tissue showing broncho-pneumonia , supurative inflammation
of the bronchiole with extension of the inflammation to the surrounding alveoli, distended alveoli
of the normal lung tissue seen at the margin.

Figure 13 : Microscopic view of lung tissue in broncho-pneumonia. Dense supurative
exudate fill the lumen of inflamed bronchiole ,extending to surrounding lung tissue .

Figure 14 : Microscopic view of lung involved in broncho-
pneumonia .

Complications of severe cases may include :
(1) Abscess formation results from tissue destruction and necrosis .
(2) Empyema which results from accumulation of suppurative material
in the pleural cavity .
(3) Organization of intra-alveolar exudate may convert areas of the
lung into solid fibrous tissue
(4) Bacteremic dissemination may lead to meningitis , arthritis or
infective endocarditis .
The complications are much more likely with serotype 3
pneumococci.

Diagnosis :
First from the symptoms ,Fever ,Rigor ,cough, difficulty in
breathing ,sputum with hemoptysis .
Chest X-ray
Examination of gram-stained sputum is an important step in the
diagnosis .
During early stages of illness, blood culture may be positive in
20%-30% of cases .
Antibiotic sensitivity test must be performed .
Commercial pneumococcal vaccines containing capsular
polysaccharides from the common serotypes of bacteria are
available, and there use in those at risk is recommended .

Haemophilus influenzae pneumonia :
Gram negative micro-organisms ,both encapsulated &
unencapsulated forms are important cause of the
community acquired pneumonia ,the former can cause a
life-threatening form of pneumonia & meningitis in children
, often following a viral respiratory tract infections .
Adults at risk of infection are those with chronic pulmonary
diseases as chronic bronchitis , cystic fibrosis and
bronchiectasis .
It is the most common cause of bacterial exacerbation in
COPD .

Moraxilla catarrhalis :
It is being recognized as a common cause of bacterial
pneumonia in the elderly , and it is the second commonest
cause of bacterial exacerbation in COPD in adults .
Staphyllococus aureus :
Is an important cause of secondary bacterial pneumonia in
children & healthy adults following viral respiratory diseases as
measles in children & influenza both in children & adults .
It is associated with high incidence of complications as lung
abscess & empyemia .
Staphylococcal pneumonia occurring in association with right
sided staphylococcal endocarditis is a serious complication of
intravenous drug abuse .

Klebsiella Pneumonia :
Is the most frequent cause of gram negative bacterial
pneumonia.
It frequently affect debilitated and mal nourished persons
particularly chronic alcoholics .
Thick & gelatinous sputum is characteristic because the
micro organism produces an abundant viscid capsular
polysaccharides, which the individual have a difficulty to
cough out .

Pseudomonas aeroginosa :
Associated with cystic fibrosis , it is most commonly seen in
nosocomial settings , it is common in people who are neutropenic
usually secondary to chemotherapy , in victims of extensive burn &
in those requiring mechanical ventilation .
Psudomonas aeroginosa have a tendency to invade blood vessels at
the site of infection with consequent intrapulmonary spread .
Pseudomonas bacteremia is a fulminant disease , death occurs
within few days .
Histological examination :
Reveals coagulation necrosis of lung parenchyma, with micro
organisms invading walls of blood vessels causing pseudomonas
vasculitis .

Figure 15 : Microscopic view of lung tissue in pseudomonas pneumonia,showing
involvement of blood vessels by bacteria ,I . e pseudomonas vasculitis & focal
infarction .

Legionella pneumophila :
Is the agent of legionnaire disease which is an epidemic &
sporadic form of pneumonia .
Pontiac fever : Is a self –limited upper respiratory tract
infection caused by L. pneumophila without pneumonic
symptoms .
Legionella pneumophila flourishes in artificial aquatic
environment such as water-cooling towers & within the
tubing systems of domestic water supplies .
The mode of transmission is thought to be either inhalation
of aerosolized organisms or aspiration of contaminated
drinking water .

It is common in persons with predisposing conditions such
as cardiac, renal or immunologic or hematologic diseases .
Organ-transplant recipients are particularly susceptible .
This type of pneumonia can be severe necessitating
hospitalization , fatality may reach 30%-50% in immuno-
suppressed individuals .
Diagnosis is by demonstration of Legionella antigen in the
urine of the patient or by fluorescent antibody test on
sputum samples .
Sputum culture is the gold standard of diagnosis .

respiratory module
part 2
audio (2)
dr.ghada al-jussani
mbchb.,frcpath (uk)
hashemite university –
faculity of medicine

II-Community-acquired atypical pneumonia :
An acute febrile respiratory disease , characterized
by patchy inflammatory changes in the lungs, largely
confined to the alveolar septa & pulmonary
interstitium .
The term atypical denotes cough with a moderate
amounts of sputum and the absence of physical
finding of consolidation & lack of alveolar exudate ..
Only moderate elevation of white cell count .

This type of pneumonia is caused by a variety of organisms
Mycoplasma pneumonia is the most common , it is
particularly common among children & young adults .
This occurs sporadically or as local epidemics in
closed communities as schools , military camps or prisons .
Other causes include viruses , as influenza type A & B , the
respiratory syncytial virus , adenovirus , rhinoviruses &
varicella virus , measles …etc.
Also Chlamydia pneumoniae and Coxiella Burnetti cause of
Q fever .

Pathogenesis :
When the organisms become attached to respiratory epithelium
followed by necrosis of the cells and inflammatory response .
In the alveoli there will be interstitial inflammation with outpouring of
fluid into alveolar spaces so that on chest X ray it may simulate
typical bacterial pneumonia .
Morphology :
Regardless to the cause , the morphologic patterns in atypical
pneumonia are similar . The process may be patchy or may involve
the whole lobe bilaterally or unilaterally .

Grossly :
The areas are red-blue, congested & the pleura is smooth uninflammed .
Microscopically :
The inflammatory reaction is largely confined to the wall of the alveoli .
The septa are widened & edematous , they usually contain mononuclear
inflammatory cells including lymphocytes, histiocytes & occasionally plasma
cells .
The alveolar spaces are free of exudate .
In full-blown diffuse alveolar damage with hyaline membrane may develop,
super imposed infection may result in mixed histological picture .
In uncomplicated cases subsidence of the disease is followed by resolution.

FIGURE 16 : MICROSCOPIC VIEW OF ATYPICAL PNEUMONIA ,SHOWING
WIDENED THICKENED ALVEOLAR SEPTA INFILTRATED BY
LYMPHOCYTES WITH PROLIFERATING PNEUMOCYTES TYPE II&
CONGESTED CAPILLARIES .

FIGURE 17 : MICROSCOPIC VIEWS OF CHRONIC ATYPICAL PNEUMONIA . SHOWING
THICKENING OF ALVEOLAR SEPTA WITH PROLIFERATING TYPE II PNEUMOCYTES
(ARROW) IN RIGHT SIDE & HYALINE MEMBRANE DEPOSITION (ARROW IN LEFT SIDE ).

FIGURE 18 : MICROSCOPIC VIEW OF ATYPICAL PNEUMONIA .

Clinically :
It is extremely variable , may simulate upper respiratory tract
infection called chest cold . It may present as a fulminant life-
threatening infection in immuno compromised individuals .
The onset is that of acute illness with fever , headache & malaise
later cough with minimal sputum, alveolar capillary block occurs
due to edema causing respiratory distress .
Test for mycoplasma antigens & polymerase chain reaction PCR
testing for mycoplasma DNA are available .

Severe Acute Respiratory Syndrome (SARS)
Caused by a previously unrecognized corona virus (SARS-
CoV) , first appear in 2002 in China then appeared in Hong Kong ,
Taiwan , Singapore , Vietnam & Toronto ., as an outbreak ,
appearing as upper respiratory tract infection ,with ability to extend
to lower respiratory tract and induce viremia .
Patient become ill after 2-10 days after exposure through person to
person contact , through secretions or feco-oral transmission , with
fever , myelgia , diarrhea , chills followed by respiratory tract
symptoms as dry cough and dyspnoea .
The lungs show diffuse alveolar damage and giant cells .

CORONA VIRUS (COVID19)
Coronavirus disease (COVID-19) is a new strain that was discovered in
2019 and has not been previously identified in humans.
Coronaviruses are zoonotic, meaning they are transmitted between
animals and people. Detailed investigations found that SARS-CoV
was transmitted from civet cats to humans and MERS-CoV from
dromedary camels to humans. Several known coronaviruses are
circulating in animals that have not yet infected humans.
Common signs of infection include respiratory symptoms, fever, cough,
shortness of breath and breathing difficulties. In more severe cases,
infection can cause pneumonia, severe acute respiratory syndrome,
kidney failure and even death.

Chest radiograph,
hospital day 3
The patient developed
rapidly progressive diffuse
opacities, worse at the lung
bases, consistent with
acute respiratory distress
syndrome (ARDS).

Standard recommendations to prevent infection spread include regular hand washing,
covering mouth and nose when coughing and sneezing, thoroughly cooking meat and
eggs. Avoid close contact with anyone showing symptoms of respiratory illness such as
coughing and sneezing.
what happens to people's lungs when they get Covid-19?
almost all serious consequences of Covid-19 feature pneumonia.
people who catch Covid-19 can be placed into four
broad categories.
The least serious are those people ho are sub-clinical and ho ha e
the virus but have no symptoms.

Next are those who get an infection in the upper respiratory tract, which, means a person has
a fever and a cough and maybe milder symptoms like headache or conjunctivitis .
Those people with minor symptoms are still able to transmit the virus but may not be
aware of it.
The largest group of those who would be positive for Covid-19, and the people
most likely to present to hospitals and surgeries, are those who develop the same
flu-like symptoms that would usually keep them off work.
A fourth group, will develop severe illness that features pneumonia.
In Wuhan, it worked out that from those who had tested positive and had sought medical
help, roughly 6% had a severe illness.
The WHO says the elderly and people with underlying problems like high
blood pressure, heart and lung problems or diabetes, are more likely to
develop serious illness.

How does the pneumonia develop?
When people with Covid-19 develop a cough and fever,They said that it is
a result of the infection reaching the respiratory tree the air passages
that conduct air between the lungs and the outside.
The lining of the respiratory tree becomes injured, causing inflammation.
This in turn irritates the nerves in the lining of the airway. Just a speck of
dust can stimulate a cough.
But if this gets worse, it goes past just the lining of the airway and goes
to the gas exchange units, which are at the end of the air passages.
If they become infected they respond by pouring out inflammatory
material into the air sacs that are at the bottom of our lungs.

If the air sacs then become inflamed, this causes an
outpouring of inflammatory material [fluid and inflammatory
cells] into the lungs and end up with pneumonia.
lungs that become filled with inflammatory material are
unable to get enough oxygen to the bloodstream, reducing
the body s ability to take on oxygen and get rid of carbon
dioxide.
That s the usual cause of death with severe pneumonia,

HOW CAN THE PNEUMONIA BE TREATED?
Unfortunately, so far we don t have anything that can stop people getting Covid-
19 pneumonia.
People are already trialling all sorts of medications and we re hopeful that we
might discover that there are various combinations of viral and anti-viral
medications that could be effective. At the moment there isn t any established
treatment apart from supportive treatment, which is what we give people in
intensive care.
We ventilate them and maintain high oxygen levels until their lungs are able to
function in a normal way again as they recover.
patients with viral pneumonia are also at risk of developing secondary infections,
so they would also be treated with anti-viral medication and antibiotics.

IS COVID-19 PNEUMONIA DIFFERENT?
Covid-19 pneumonia is different from the most common cases that
people are admitted to hospitals for.
Most types of pneumonia that we know of and that we admit people to
hospital for are bacterial and they respond to an antibiotic. there is
evidence that pneumonia caused by Covid-19 may be particularly
severe. cases of coronavirus pneumonia tend to affect all of the lungs,
instead of just small parts.
Once we have an infection in the lung and, if it involves the air sacs,
then the body s response is first to try and destroy [the virus] and limit
its replication.

generally, people aged 65 and over are at risk of getting pneumonia,
as well as people with medical conditions such as diabetes, cancer or
a chronic disease affecting the lungs, heart, kidney or liver, smokers,
and infants aged 12 months and under.
Age is the major predictor of risk of death from pneumonia.
Pneumonia is always serious for an older person and in fact it used to
be one of the main causes of death in the elderly. Now we have very
good treatments for pneumonia.
I im o an o emembe ha no ma e ho heal h and ac i e o
are, your risk for getting pneumonia increases with age.This is
because our immune system naturally weakens with age, making it
ha de fo o bodie o figh off infec ion and di ea e .

III- Nosocomial pneumonia :
( Hospital-acquired pneumonia )
Is pulmonary infections acquired in the course of hospital
stay .
It is common among hospitalized patients with severe
underlying disease , immune suppression or prolonged
antibiotic therapy .
Those on mechanical ventilation represent a high risk group
.
Gram negative rods like enterobacteria & pseudomonas sp.
& staph. Aureus are the most common isolates

IV- Aspiration pneumonia :
Caused by aspiration of gastric contents either while
patient is unconscious or during repeated vomiting .
The resultant pneumonia is partly chemical resulting
from the extremely irritating effect of gastric acid , and
partly bacterial .
It is a necrotizing pneumonia may be fatal especially in
debilitating patients, but in those who survive
complications like abscess formation & foreign-body
giant cell granulomas are common .

FIGURE 19 : GROSS VIEW OF LUNG IN ASPIRATION PNEUMONIA SHOWING
NUMEROUS ABSCESSES DARK GRAY IN COLOR .

FIGURE 2 0 : MICROSCOPIC VIEW OF LUNG IN ASPIRATION PNEUMONIA, SHOWING
GASTRIC CONTENT WITH INFLAMMATORY CELLS & MACROPHAGES ,SEEN WITHIN
ALVEOLI,

FIGURE 22 : MICROSCOPIC VIEW OF ASPIRATION PNEUMONIA , SHOWING
MACROPHAGES & INFLAMMATORY CELLS SURROUNDING ASPIRATED GASTRIC
CONTENT .

V- Lung abscess :
A localized area of suppurative necrosis within pulmonary parenchyma .
Introduction of causative organisms may arise in the following mechanisms :
1- Aspiration of infective material from carious tooth, infected sinuses or tonsils ,
particularly during oral surgery , anesthesia , coma or alcoholic intoxication & in
debilitated patients with depressed cough reflex .
2- As complication of necrotizing bacterial pneumonia & mycotic lung infections .
3- Bronchiectasis .
4- Following bronchial obstruction as in tumors .
5- Septic embolism from septic thrombophlebitis or infective endocarditis .
6- Impaired drainage .
7- In bacteremia .

Morphology :
Abscesses vary from few millimeters to large cavities 5-6 cm.
in diameter .
The number & localization of the abscesses depend on the
mode of their development .
Abscess resulting from aspiration of infective material are
more common on the right side and is single , it tends to
occur in the posterior segment of upper lobe & in in the
apical segment of the lower lobe, because these locations
represent a probable course of aspirated material when the
patient is recumbent .

Abscesses that develop in the course of pneumonia or
bronchiectasis are commonly multiple , basal & diffusely
scattered .
Septic emboli & abscesses arising from hematogenous seeding
are commonly multiple & may affect any region of the lungs .
As the focus of suppuration enlarges the abscess inevitably
ruptures into airways thus exudate may be partially drained ,
producing air-fluid level on radiological examination.
Occasionally the abscess may rupture into the pleural cavity and
a broncho-pleural fistula develops the consequences are
pneumothorax or empyema .

FIGURE 23 : GROSS APPEARANCE OF LUNG ABSCESSES (ARROWS) ,SHOWING
IRREGULAR-SHAPED CAVITIES WITHIN LUNG PARENCHYMA FILLED WITH NECROTIC &
HEMORRHAGIC TISSUE .

Other complications are the embolization of septic material to the brain
giving rise to meningitis and brain abscess .
Histologically :
There is supurative inflammation surrounded by fibrous scarring &
mononuclear cells infiltration including lymphocytes, plasma cells &
macrophages.
Clinical course :
The manifestation of a lung abscess are much like those of bronchiectasis
like cough with copious amount of foul - smelling sputum , hemoptysis may
occur . Fever , malaise are common, clubbing of fingers , weight loss &
anemia . Infective abscesses occur occur in 10%-15% of bronchogenic
carcinoma .
Secondary amyloidosis may develop in chronic cases.

CHRONIC PNEUMONIA
PNEUMONIA IN THE
IMMUNOCOMPROMISED HOST

VI- Chronic pneumonia
Tuberculosis :
Is a communicable chronic granulomatous disease caused by
Mycobacterium Tuberculosis . It usually involves lungs , but may
affect any organ .
Epidemiology :
1.7 billion individuals are infected worldwide, with 8-10 million new cases and
million deaths per year .
TB is common among medically & economically deprived persons . It flourishes
whenever, there is poverty, crowding& chronic debilitating illness .
Elderly people , those with diabetes, chronic renal diseases , chronic
heart disease, malnutrition alcoholism, and immunosuppression , such as HIV
infection .

Infection with Mycobacterium tuberculosis typically
leads to the development of delayed hypersensitivity
which can be detected by Tuberculin ( Mantoux ) test
After 2-4 weeks after infection has begun ,
intracutaneous injection of 0.1ml. of purified protein
derivative (PPD) induces a visible & palpable
induration ( at least 5 mm. in diameter ) that peaks in
48-72 hours .
A positive tuberculin test results signifies cell-
mediated hypersensitivity to tuberculous antigens .

Etiology :
Mycobacteria are slender rods that are acid fast i.e. that
have high content of complex lipid that readily bind the
Ziehl-Neelsen stain and subsequently stubbornly resists
decolorization .
M.Tuberculosis Hominis is responsible for most cases of
tuberculosis .The reservoir of infection usually found in
humans with active pulmonary disease .
Transmission is usually direct by inhalation of airborn
organisms in airosoles generated by expectoration .

Orophangeal & intestinal TB contracted by drinking contaminated milk
with Mycobacterium Bovis , still seen in countries that have tuberculous
dairy cow & unpasturized milk .
Mycobacterium avium-intercellulare are much less virulent than M.
Tuberculosis & rarely cause disease in immunocompetent persons . It
affects patients
with AIDS in 10%-30% .
Pathogenesis :
In previously unexposed immunocompetent patients is centered on the
development of a targeted cell- mediated immunity that confers resistance
to the organism & result in tissue hypersensitivity to TB antigen , such as
caseating granuloma & cavitation are the result of the destructive tissue
hypersensitivity reaction .

Once virulent strain of Mycobacteria gains entry into the
macrophage , the organism is capable of inhibiting normal
microbicidal responses by manipulation of endosomal PH & arrest
endosomal maturation , leading to impairment of effective
phagolysosome formation & unhindered microbial proliferation ..
Thus the earliest phase of primary TB in the non-sensitized
individuals is characterized by bacillary proliferation within the
pulmonary alveolar macrophages & airspaces with resulting
bacteremia & seeding in multiple sites .
Despite the bacteremia the patients are asymptomatic or have a mild
flu-like illness .
The cell-mediated immunity develops 3 weeks after exposure .

Processed mycobacterial Ag reaches the regional lymph nodes & are
presented in a major histocompatibility class II context by dendritic cells
macrophages to CD4+ T cells ( helper T lymphocyte).
Under the influence of macrophages secreted IL-12 CD4+T cells are
gene a ed capable of ec e ing IFN
Activated macrophages , in turn release variety of mediators with
important down stream effects like TNF which is responsible for
recruitment & activation of monocytes then differentiation into
epithelioid histiocytes that characterize the granulomatous reaction .
Nitric oxide (NO) a powerful oxidizing bactericidal agent & Generation of
reactive oxygen species (ROS) that have antibacterial activity.

FIGURE 24 : SCHEMATIC DEMONSTRATION OF PATHOGENESIS OF
PRIMARY TB.

Primary Tuberculosis :
Is the form of disease that develops in a previously
unexposed & therefore unsensitized person .
Elderly persons & immunosuppressed persons
may loose their sensitivity to the TB bacilli so may
develop multiple primary TB. In the primary TB the
source of organism is exogenous .
5% of those newly infected develop significant
disease .

Morphology :
The inhaled bacilli are drained into distal airspaces of the lower
part of the upper lobe & upper part of the lower lobe usually close
to the pleura
A sensitization develops a 1-1.5 cm. area of gray white
inflammatory consolidation emerges the Ghon focus , in most
cases the center of this focus undergoes caseous necrosis .
TB bacilli either free or within macrophages drained to the regional
lymph nodes which also caseats .
This combination of paranchymal lesion and nodal involvement is
referred to as the Ghon complex .

During the first few weeks there is also hematogenous & lymphatic
dissemination to other parts of the body .
In 95% of cases development of cell-mediated immunity controls the
infection.
Hence the ghon focus undergoes progressive fibrosis often followed
radio logically detected calcification & despite dissemination to
other organs no lesion develop.
Histologically :
Sites of active involvement are marked by granulomatous
inflammatory reaction with caseating tubercles which are
microscopic may coalesce to be seen macroscopically , the
granuloma is surrounded by fibroblastic rim .

FIGURE 25 : GROSS APPEARANCE OF LUNG SHOWING GOHN COMPLEX OF PRIMARY TB
. A SMALL SUB PLEURAL WHITE NODULE (GOHN FOCUS) & A CASEATING HILAR LYMPH
NODE NEAR THE MAJOR BRONCHUS .

Secondary TB = Reactivation TB
A pattern of disease that arises in a previously sensitized host . It may follow shortly
primary TB or commonly arises many decades after the initial infection due to
lowered host immunity resulting from reactivation of dormant primary TB .
It may result from exogenous infection .
Secondary TB is classically localized to the apex of one or both lobes . Related to
high oxygen tension .
Because of the pre existence of hypersensitivity the bacilli excite a prompt and
marked tissue responses that tend to wall off the focus .
The regional lymph nodes are less prominently involved early in the developing
disease than they are in primary TB . Cavitation occurs readily in the secondary form
resulting in dissemination along the airways and this is important source of
infectivity because the patient now raises sputum containing bacilli.

Morphology :
The initial lesion is usually a small focus of consolidation within 1-2
cm. in diameter of the apical pleura which are sharply circumscribed
firm gray-white to yellow areas that have a variable amount of
caseous necrosis & peripheral fibrosis .
In favorable cases, the initial paranchymal focus undergoes
progressive fibrous encapsulation leaving only fibrocalcific scar.
Histologically :
The active lesion show characteristic coalescent tuberculous
granuloma with Langhan’s giant cells and central caseation .TB
bacilli can be demonstrated in early lesions but it is almost
impossible to find them in the late stage .

FIGURE 26 : GROSS APPEARANCE OF LUNG IN SECONDARY TUBERCULOSIS ,SHOWING
BILATERAL CAVITATING TB GRANULOMAS AT

FIGURE 27 : MICROSCOPIC VIEW OF TB GRANULOMA WITH LANGHAN’S GIANT CELL
SHOWING HORESE-SHOE LIKE NUCLEAR ARRANGEMENT .

FIGURE 28 : MICROSCOPIC VIEW OF PULMONARY CASEATING. ‫ز‬TUBERCULOUS
GRANULOMA

MICROSCOPIC VIEW OF CASEATING TB GRANULOMA
.

The apical lesion may heal spontaneously or by
therapy or may extend along different pathways :
1- Progressive pulmonary TB :
The apical lesion enlarges with expansion of the
area of caseation .
Erosion into the bronchus evacuate the caseous
center creating an irregular cavity bounded by
caseation material that are poorly walled by
fibrous tissue .

With adequate treatment the process may be arrested
although healing by fibrosis distort the pulmonary
architecture .
Irregular cavities now free of caseation necrosis , may
remain or collapse in the surrounding fibrosis .
If the treatment is inadequate or if host defenses are
impaired , the infection may spread by direct
expansion , via dissemination through airways ,
lymphatic channels or the vascular system .

FIGURE 30 :
GROSS
APPEARANCE
OF LUNG IN
PROGRESSIVE
PULMONARY
(SECONDARY)TB
SHOWING
MULTIPLE
WHITE TB FOCI
& APICAL
CAVITY .

2- Miliary pulmonary TB :
Occurs when the organisms drain through lymphatics into
the lymphatic ducts which eventually empty into the
venous return to the right side of the heart & thence into
the pulmonary artery .
Individual lesions are either microscopic or small visible
(2-3 mm.in diameter ) foci of yellow white consolidation ,
scattered through the lung parenchyma .
Miliary lesions may expand & coalesce to yield almost
total consolidation of large lesion or even the whole lobe .

FIGURE 31 : GROSS APPEARANCE OF LUNG SHOWING FEATURES OF MILIARY TB.
HUNDREDS OF MINUTE WHITE TB GRANULOMAS SEEN ALL OVER LUNG TISSUE .

3- TB Pleurisy :With progression pulmonary TB
may involve the pleura resulting in a serous
pleural effusion within pleural cavity , TB
empyema or obliterative fibrous pleuritis may
develop .
4- Endobronchial, endotracheal & laryngeal TB
May develop when infective material is spread
either through lymphatic channels or from
expectorated infectious material .

5- Systemic military TB :
When infective foci in the lung seed the pulmonary
venous return to the heart the organism subsequently
disseminated through the systemic arterial system .
Almost any organ in the body may be seeded .
Lesions resemble those in the lungs may be seen in
the heart , liver , bone marrow , spleen , adrenals ,
kidneys , meninges , fallopian tubes & epididymis .

CHEST X-RAY APPEARANCE OF PLEURAL EFFUSION IN PLEURAL TB

Clinically :
Localised secondary TB may be asymptomatic systemic manifestations may
be insidious in onset it is related to cytokines released by macrophages TNF
& IL-1 often appear early in the course of illness including malaise ,
anorexia , weight loss , fever & night sweat . Pleuritic pain may result from
pleural involvement .
Diagnosis :
The most common method is the demonstration of acid fast bacilli
Zeihl-Neelsen stain or by fluorescent auramine rhodamine method
should be done on two consecutive sputum specimens .
Sputum culture usually takes 10 weeks.
PCR method for TB bacilli DNA recently used.

ZEIHL-NEELSEN STAIN FOR TB BACILLI (ACID FAST BACILLI)
MYCOBACTERIUM TB.

ZEIHL-NELSEN STAIN FOR TB BACILLI (ACID FAST BACILLI)
MYCOBACTERIUM TB.

respiratory module
part 2 audio (3)
dr.ghada nazar al-jussani
mbchb.,frcpath (uk)
faculty of medicine ,hashemite
university

VII- Pneumonia in the immunocompromized host :
A wide variety of so called apportunistic agents
many of which rarely cause infection in normal host ,
can cause these pneumonias :
1- Bacteria : like pseudomonas aeroginosa
Mycobacteria sp., Legionella pneumophila & Listeria
monocytogenes .
2- Viruses : cytomegalovirus & herpes virus .
3- Fungi : Candida, Aspergillus & cryptococcus neoformans .

Cytomegalovirus Infections :
A member of herpes virus family .
Cells infected by the virus exhibit gigantism of both the nucleus & cytoplasm ,
within the nucleus an inclusion surrounded by a clear halo giving an owl-eye
appearance . It may involve any organ in the body .
Transmission of the virus can be either :
- Trans placental to the fetus causing congenital CMV.
- Breast milk & through vaginal & cervical secretions .
- Respiratory transmission .
- Feco - oral route .
- Iatrogenic transmission through organ transplant or blood transfusion .

Microscopic view of Cytomegalovirus infection of lung showing owel-eye appearance of CMV
inclusion and proliferating (arrow ). pneumocytes type II

Microscopic view of cytomegalovirus pneumonia , showing lymphocytic cells ,macrophages & viral inclusions
(arrows

Microscopic view of viral pneumonia ,showing cytomegalo viral inclusions .

Microscopic view of viral pneumonia ,showing viral inclusions & giant cells .

Clinically :
The most common clinical presentation is the mononucleosis
– like illness with fever atypical lymphocytosis ,
lymphadenopathy , hepatomegally & hepatitis .
It may affect the lungs , CNS ,bone marrow , GIT & Retina .
In pulmonary infection an interstitial mononuclear cells
infiltrate with foci of necrosis , accompanied by the typical
viral inclusion .
The lesion may progress to full-blown acute respiratory
distress syndrome (ARDS) .

Pneumocystis Pneumonia :
Pneumocystis jeroveci previously used to be called
pneumocystis Carinii long considered as a protozoa
.. it is found to be more closely related to fungi .
It is extremely common in patients with AIDS .
It classically decrease the number of CD4 helper T
lymphocytes in blood .
Infection is largely confined to the lungs with
production of interstitial pneumonia.

Microscopically :
Involved area of the lung demonstrate a characteristic
intra-alveolar foamy pink- staining exudate , the septa
are thickened by edema & minimal mononuclear cells
infiltrate Silver stain demonstrate the organism either
the trophozoite or the cyst form , the cup-shaped cyst
wall ,
while Giemsa or methylene blue can demonstrate the
trophozoite form
Clinically :
Fever , cough & dyspnoea .

Silver stain showing cystic form of Pneumocystis jiroveci .

High power view of Pneumocystis juroveci ,

Candidiasis :
Candida albicans is the most frequent disease causing fungus , it is
a normal inhabitant of the oral cavity. Candidiasis with pneumonia
is a disease confined to the immunocompromised patients .
Morphology :
In tissue sections Candida albicans demonstrate a yeast – like
forms, pseudo & true hyphae can be seen by Gomori methenamine
silver stain and periodic acid Schiff (PAS) stain .
Candida pneumonia usually presents as bilateral nodular infiltrate
resembling pneucystis pneumonia.

Lung Tumors
Lung Tumors
Classify lung tumors
Describe the etiology , pathogenesis, pathologic
features& routes of spread of the four types of
lung cancer :
Squamous cell Ca,
Adenocarcinoma .,
Large cell carcinoma .
& small cell carcinoma .

Lung Tumors :
Although the lungs are frequently the site for metastases primary
lung cancer is also a common disease .
Bronchial epithelium is the site of origin of 95% of the primary lung
tumors.
5% are miscellaneous group including carcinoid ,and mesenchymal
malignancies .
The most common benign tumor of the lung is the hamartoma .
Carcinoma of the lung is number one cause of cancer-related deaths
in industrialized countries .

Lung cancer is the cause of 1.4 million deaths
worldwide/yearly . (WHO 2007) .
25% of all cancer death is due to lung cancer in USA.
The American cancer society estimates that in 2006 ,
172,570 individuals were diagnosed with lung cancer and
163,510 will die from it .
According to the Jordan Cancer Registry
2011 , lung cancer ranks the forth of the ten
most common cancers among both genders , being the
first cancer among males 2011 .

The rate of lung cancer among men is declining but it
continues to accelerate among women with more women
dying from lung cancer than breast cancer , since 1987 .
There is a close relation of lung cancer incidence &
smoking .
The peak incidence is seen in persons between 50-60
years .
More than 50% have distance metastasis at the time of
diagnosis .
The 5 years survival is 15% .

Diagram showing hilar tumor of lung .

Gross view of hilar lung cancer located at the hilum of the lung .

Lung cancer can present as a
I- Hilar tumor arising from major bronchi,like squamous cell Ca.,
small cell anaplastic Ca. or Adenocarcinoma .
II- Peripheral tumors ,like large cell anaplastic ca, or bronchiolo-
alveolar Ca.
Four histological types of lung cancer :
Squamous cell carcinoma .
Adenocarcinoma
Small cell anaplastic carcinoma
Large cell anaplastic carcinoma.
Combined cancer can occur together like squamous cell ca. &
adenoca.

Adenocarcinoma is by far the commonest cancer among women , in
non-smoker and in young persons before 45 years of age .
For therapeutic purposes : lung cancer are classified into :
* Small cell lung cancer(SCLC)
* Non-small cell lung cancer (NSCLC) which includes
Sq.c.ca.,Adenoca.,Large cell ca.
This is because all SCLC have metastasized at the time of diagnosis & hence
not curable by surgery therefore they are best treated by chemotherapy with
or without radiation .
In contrast to NSCLC usually respond poorly to chemotherapy & are better
treated by surgery .

Etiology & pathogenesis :
Inactivation of the putative tumor suppressor gene located
on short arm chromosome 3 is very early event .
Whereas P53 mutation or activation of the KRas oncogene
occurs relatively late .
The carcinogenic effect of cigarette smoke & other
environmental insults are responsible for the genetic
alteration in lung cancer .
There is a linear relation between the frequency of lung
cancer and pack-years of cigarette smoking

The increased risk becomes 60 times greater among
habitual heavy smokers
( 2 packs/day) for 20 years compared to non-
smokers .
The clinical evidence is largely composed of
documentation of progressive morphologic
alterations in the lining epithelium of the
respiratory tract in habitual cigarette smokers
mostly for sq, c. ca ., including basal cell
hyperplasia , dysplasia & carcinoma in situ .

Increased incidence of lung cancer among miners of
radioactive ores ,asbestos workers & in workers
exposed to dust containing nickel , vinyl chloride &
mustard gas .
Exposure to asbestos increases the risk to lung
cancer 5 folds in non-smokers , by contrast heavy
smokers exposed to asbestos have an
approximately 55 times greater risk of lung cancer
than do non-smokers not exposed to asbestos .

A subset of adenocarcinoma ,particularly arising
in non-smoking women of Far east origin , is due
to mutation of epidermal growth factor
receptor (EGFR) . Combined EGFR & K-RAS
mutations occurs in 30% of such cancers.
Other mutations can also be identified which
can be useful in determining the selection of
theraputic drugs .

Morphology :
Lung cancer begins as a small mucosal lesions that are
usually gray white may form intra luminal masses or form
large masses pushing into adjacent lung parenchyma .
Some large tumors undergo central cavitation caused by
necrosis & hemorrhage .. Finally those tumors extend to
the pleura & chest wall & involve the intra thoracic
structures .
More distant spread occurs via the lymphatics or via
hematogenous route .

Squamous cell carcinoma :
More common in men than in women
Closely related to smoking .Arises centrally
in major bronchi & spread to hilar lymph
nodes .
Large lesions undergo central necrosis &
cavitation.
Preceded by squamous metaplasia,
dysplasia & carcinoma in situ .

Diagnosis :
Done by cytological examination of sputum smear which shows
malignant cells , malignant squamous cells & anaplastic small
carcinoma cells are easily detached & shed thus can be identified
easily in sputum specimens .
Also by bronchial lavage & brush.
Endoscopic bronchial biopsy is even more accurate .
Histologically :
Ranges from well differentiated squamous cell carcinoma showing
keratin pearls & intercellular bridges , to poorly differentiated
having minimal resemblance to squamous cells

Gross appearance of lung showing a large white tumor (squamous cell carcinoma
)arising in major bronchus extending to the pleural surface .

Adenocarcinoma :
May occur as a central lesion like squamous cell carcinoma
or peripherally located & presents as pneumonic
consolidation grossly & radiologically , clinically presents
as unresolved pneumonia.
This tumor may arise in relation to a peripheral scar ,thus
called scar cancer
It is most common cancer in women & non- smokers .
They tend to grow slowly & form small masses .
They tend to metastasize early .

Histologically :
May assume variable forms .
Acinar gland forms, papillary, or solid which
requires demonstration of intracellular mucin .
Foci of squamous cell carcinoma may be present .
The putative precursor for peripheral
adenocarcinoma is atypical adenomatous
hyperplasia .

Microscopic views of lung tissue showing atypical adenomatous hyperplasia ,which is
considered as a precursor lesion for adenocarcinoma

Gross view of lung showing adenocarcinoma looking as a peripherally located white tumor in the
left lower lobe .

Gross appearance of left lung, showing peripherally located
adenocarcinoma a whitish tumor at the lower lobe .

Microscopic view of lung tissue showing well
differentiated adenocarcinoma .

Microscopic appearance of high power view of bronchiolo-alveolar
carcinoma of the lung .

In situ pulmonary adenocarcinoma (AIS) Bronchiolo-alveolar
carcinoma
is a subtype of lung adenocarcinoma.
It tends to arise in distal bronchioles or alveoli and is defined by a non-
invasive growth pattern.
This small solitary tumor exhibits pure alveolar distribution (lepidic growth)
and lacks any invasion of the surrounding normal lung. If completely removed
by surgery, the prognosis is excellent with up to 100% 5-year survival .
They involve the peripheral part of the lung, either as a single nodule or
more pneumonia-like consolidation
The characteristic feature is their growth along pre-existing structures and
preservation of alveolar architecture .
The tumor cells grow in monolayer on top of alveolar septa which serves as a
scaffold .

Bronchioloalveolar carcinoma (BAC) is a variant of non-small cell lung cancer
(NSCLC) that in recent years has received a new identity and nomenclature
from the histology perspective.
Salient Features of the Revised Classification of 2011
Removal of the term bronchioloalveolar carcinoma and hence its subtypes of
mucinous and non-mucinous
Replacement of the prior bronchioloalveolar carcinoma with adenocarcinoma in situ
(AIS)
Introduction of a minimally invasive adenocarcinoma with lepidic growth with less
than 5 mm invasive component
A size limit of 3 cm to non- or minimally invasive adenocarcinoma

It is therefore important to remember that the terms "bronchioloalveolar
carcinoma " and "adenocarcinoma with lepidic growth" are not synonyms but a
reflection of our evolved histologic understanding of a less aggressive form of
adenocarcinoma overall.
Histomorphological Overview of Current Tumors in Adenocarcinoma
with Lepidic Growth
Atypical Adenomatous Hyperplasia (AAH)
Less than 0.5 cm, localized areas of hyperplasia of type 2 pneumocytes and/or
Clara cells replacing normal alveolar epithelium.
Adenocarcinoma in Situ (AIS)
The closest to the previous non-mucinous BAC. Less than 3 cm, solitary nodules
with pure lepidic growth with somewhat higher cellular atypia than AAH.
They have small monomorphous nuclei with pinpoint nucleoli and occasional
nuclear inclusions.

Minimally Invasive Adenocarcinoma (MIA)
Less than 3 cm solitary lesions with lepidic growth pattern
with less than 5 mm areas of invasive foci in addition.
The invasive component can be uni- or multifocal and can be
of any histologic pattern other than lepidic (papillary,
micropapillary, acinar, or solid).
By definition, they do not have any evidence of vascular,
stromal, or pleural invasion.
It can be challenging at times to distinguish alveolar collapse
from stromal invasion, and elastin stains can be of use.

Lepidic Predominant Adenocarcinoma (LPA)
Adenocarcinoma with areas of lepidic growth and greater than 5 mm
invasive foci or evidence of invasion of stroma with blood vessel,
pleura, or lymphatic invasion or necrosis. A higher percentage of
lepidic growth patterns were associated with lower risk of recurrence.
Multiple studies have demonstrated that the invasive component size
and the histomorphologic subtype are better predictors of survival than
total tumor size.
Cytological features include a flat sheet of homogenous neoplastic cells
with mild nuclear enlargement and prominent nuclear grooves.
In case of minimally invasive adenocarcinoma, apart from the lepidic
growth pattern, the invasive component is represented by papillary or
acinar growth patterns in the center or periphery of the tumor mass.

Gross view of bronchiolo-alveolar carcinoma (adenocarcinoma in situ) looking
like unresolved pneumonia with consolidation of three lobes of right lung .

Gross view of lung showing bronchiolo-alveolar carcinoma
(adenocarcinoma in situ) .

Microscopic view of bronchiolo-alveolar carcinoma (adenocarcinoma in situ)
malignant cells grow in monolayer on top of alveolar septa which serves as a
scaffold

Microscopic view of bronchiolo-alveolar carcinoma (adenocarcinoma
in situ) of the lung .

High power view of bronchiolo-alveolar carcinoma
(adenocarcinoma in situ) .

respiratory module
part2 audio (4)
dr.ghada al-jussani
mbchb.,frcpath (uk)
faculity of medicine , hashemite
university

Large cell Anaplastic carcinoma :
Undifferentiated malignant epithelial tumor that lacks the
cytological features of small cell ca., squamous cell ca. or
adenocarcinoma ..
The cells have large nuclei, prominent nucleoli and
moderate amount of cytoplasm .
Sometimes even giant cells may be seen .
The tumor is highly malignant tumor , tends to be
peripheral in location .

Microscopic view of large cell anaplastic ca. of lung .

Large cell anaplastic carcinoma of the lung .

Small cell carcinoma :
Appear as a pale gray centrally located mass with
extension to the lung parenchyma & early involvement of
the hilar & mediastinal lymph nodes .
The tumor is composed of rounded or fusiform cells scanty
cytoplasm and finely granular chromatin , mitotic figures
are numerous . The cells show fragmentation .
The tumor cells are derived from neuro-endocrine cells of
the lung they produce neuron-endocrine markers &
paraneoplastic syndromes , suggesting that it is derived
from multipotent proginator cells .

Gross appearance of centrally located small cell anaplastic ca. of lung ,with
involvement of hilar lymph nodes (arrow).

Microscopic view of small cell anaplastic carcinoma
of the lung .

Microscopic view of small cell anaplastic ca. of lung showing sheets & ribbons of
closely-packed malignant rounded cells.

Cytological smear of sputum from patient with anaplastic small cell ca. (oat cell
type) showing closely- packed cells .

Clinically :
Cancer of the lung is silent, insidious , patient may have
chronic cough , & expectoration of bloody sputum
(hemoptysis) , by time hoarseness of voice chest pain ,
pericardial & pleural effusion , atelactasis & pneumonitis .
Apical tumors can invade the brachial plexus & cervical
sympathetic plexus to cause sever pain in the distribution
of ulnar nerve to produce Horner syndrome an epsilateral
enopthalmos , ptosis , miosis and anhidrosis .
This tumor is called Pancoast tumors and the combination
of the clinical syndrome is called pancoast syndrome .

Diagnosis
Immunohistochemistry is a widely available technique that is less
challenging and can provide clinically meaningful results quickly and
cost-efficiently in comparison with other techniques.
In addition, immunohistochemistry allows for the evaluation of
cellular localization of proteins in the context of tumor structure
pathologists are required to classify lung cancer into specific
subtypes and assess biomarkers relevant to molecular-targeted
therapies. immunohistochemistry in lung cancer, including (i)
adenocarcinoma vs squamous cell carcinoma; (ii) neuroendocrine
markers; (iii) ALK, ROS1, and EGFR; (iv) PD-L1 (CD274); (v) lung
carcinoma vs malignant mesothelioma;

Before the 2015 WHO classification, the definition of
adenocarcinoma and SqCC were based on their morphological
features with or without mucin staining. Adenocarcinoma was
defined as carcinoma with an acinar/tubular structure or
mucin production, whereas SqCC was defined as carcinoma
with keratinization or intercellular bridges.
In the current classification, a solid carcinoma without
glandular structures or mucin production, but with
immunohistochemical positivity for adenocarcinoma
markers , i.e., TTF-1 (NKX2-1) and/or Napsin A, is diagnosed as
an adenocarcinoma.

Similarly, a solid carcinoma without
keratinization or intercellular bridges, but with
immunohistochemical positivity for SqCC
markers , such as p40, CK5/6, and TP63 (p63), is
diagnosed as SqCC.
These modifications using immunohistochemical
evaluations have markedly minimized the
proportion of NSCLC diagnosed as large cell
carcinoma

In small biopsy specimens with crush artifact, separating
small cell carcinoma from poorly differentiated squamous
cell carcinoma with or without small cell features is a
problem.
The markers that have been used are TTF -1 and p63 (a
nuclear basal cell marker and a member of the p53 family
involved in development of epithelial tissues)19 and CK5 and
CK8.
Small cell carcinomas are predominantly TTF -1 positive
(90%), p63 negative, CK5 negative, and CK8 positive, and
squamous cell carcinomas are typically TTF -1 negative
(90%), p63 positive, CK5 positive, and CK8 negative.

Genetic Mutation and Testing in Lung Cancer
Cancers occur when genetic mutations build up in critical
genes, specifically those that control cell growth and division
(proliferation) or the repair of damaged DNA.
These changes allow cells to grow and divide uncontrollably
to form a tumor.
In nearly all cases of lung cancer, these genetic changes are
acquired during a person's lifetime and are present only in
certain cells in the lung.These changes, which are called
somatic mutations, are not inherited.

Somatic mutations in many different genes have been found
in lung cancer cells. In rare cases, the genetic change is
inherited and is present in all the body's cells (germline
mutations).
Somatic mutations in the TP53, EGFR, and KRAS genes
are common in lung cancers
EGFR (the gene that produces a protein called
epidermal growth factor receptor) is abnormal, or
mutated, in about 10% of patients with non-small cell
lung cancer and in nearly 50% of lung cancers arising in
those who have never smoked.

Patients with cancer that has an EGFR mutation generally
respond positively to treatment with the drug erlotinib
(Tarceva®).
If your tumor has an EGFR mutation, your doctor may
recommend treatment with this drug or participation in a
clinical trial.
Another mutation we regularly test for is in a gene
called KRAS.
KRAS is mutated in about 25 % of patients with non-small
cell lung cancer. If your tumor has a mutation in KRAS, your
doctor may recommend a clinical trial specifically designed
for patients with KRAS mutations.

Small cell lung cancer (SCLC) is the most aggressive
subtype of lung cancer, characterized by a 5-year
survival rate of <7%.
Considering that standard treatments have not
changed in decades, a deeper understanding of
cellular and molecular mechanisms underlying SCLC
initiation, progression, metastasis and acquisition of
resistance is required to improve the available
treatment options.

Extensive genomic analyses have been carried out and there
is a panel of several genes that appear mutated/abnormal
in nearly all SCLCs, such as p53, Rb and Myc family
members.
In addition, certain oncogene mutations such as KRAS are
rare or non-existent.
Predominant mutations observed in SCLC include loss-of-
function mutations in the Rb and p53 genes.
Overexpression of proto-oncogenes by amplification of
distinct chromosomal regions include L-myc or C-myc

Paraneoplastic syndromes :
3%-10% of patients with cancer develop clinically overt
paraneoplastic syndrome :
(1) Hypercalcemia due to increased PTH by squamous cell carcinoma
(2) Cushing syndrome due to secretion of ACTH by sq,c. ca .
(3) ADH by squamous cell ca.
(4) Neuromuscular syndromes like myasthenia syndrome , peripheral
neuropathy & polymyositis
(5) Clubbing of fingures & hypertrophic pulmonary osteoarithropathy
(6) Migratory thrombophlebitis .By adenocarcinoma

Bronchial Carcinoid :
Constitute 5% of lung tumors .
Arise from the Kulchisky cells ( neuroendocrine cells) that lines the
bronchial mucosa.
The neoplastic cells contain dense –core neurosecretory granules in the
cytoplasm .
May be part of multiple endocrine neoplasia MEN syndrome .
Carcinoid appear early in age of 40 years.
Carcinoids are generally resectable & curable.
Arise in the main stem bronchus may produce obstructive polypoid lesion or
mucosal plug penetrate the bronchial wall into peribronchial tissue
producing what is called collar-button lesion .
5%-15% give metastases to hilar lymph nodes .
Rarely distant metastases .

Endoscopic view of bronchial carcinoid polypoid tumor occluding the
lumen.

Microscopic view of carcinoid tumor .

Electron microscopic picture of carcinoid tumor showing electron-dense
neurosceretory granules (arrows).

Pleural lesions & mesothelioma
Laryngeal tumors

Pleural Effusion :
Is the presence of fluid in pleural space Can be transudate as in
chronic heart failure .Called hydrothorax .
Can be exudate as in pleuritis .
Empyema when pus accumulates .
Pneumothorax , or
Chylothorax , which is accumulation of thick white milky fluid i.e
lymph , due to rupture of lymphatic ducts .
Hemothorax ; when blood accumulates within pleural cavity
,usually traumatic during chest trauma , rib fracture , surgery or
malignant tumors .

Diagram showing pleural effusion .

Gross view of hemorrhagic pleural effusion .Fresh blood fills pleural cavity
causing lung collapse .

Malignant mesothelioma
Is a rare carcinoma of mesothelial cells .
Arises in visceral pleura or parietal pleura ,
also in the pericardium or peritoneum .
It is related to occupational exposure to
asbestos in 50% of patients with this tumor
( ship-yard workers, minors , insulators ) .

Morphology :
The tumor ensheaths the pleura causing diffuse thickening of the
pleura , it is usually preceded by progressive pleural fibrosis & pleural
plaque formation .
Histologically :
Can be of three forms either :
I- Epithelial showing glandular structures.
II- Sarcomatous consisting of malignant
spindle cells.
III-Biphasic when both elements are seen .

Gross appearance of mesothelioma of pleura ,the white tumor ensheathes
the whole lung .

Microscopic view of epithelial mesothelioma .

Microscopic view of sarcomatous spindle cell mesothelioma .

Nasopharyngeal carcinoma :
Rare neoplasm
Has strong epidemiologic link to EB virus
High frequency among Chinese.
It has three histological features :
Keratinizing squamous cell carcinoma .
Non-keratinizing sq.c. ca.
Undifferentiated carcinoma: which is the most common & closely linked
to EBV .
It is associated with striking influx of mature T lymphocytes surrounding
syncytial sheets of malignant epithelial cells .
They are called lymphoepithelioma .
It is a radiosensitive . The 5 years survival is 50%.

Microscopic view of nasopharyngeal carcinoma showing poorly
differentiated squamous cells mixed with lymphocytes ,called
lymphoepithelioma .

Laryngeal tumors :
Vocal cord nodule or polyp :
a smooth hemispherical protrusions less than 0.5 cm.
in diameter located on true vocal cord .
The nodule is covered by stratified squamous
epithelium. That is usually intact but it may ulcerate .
The tumor tend to occur among smokers & singers
called singer's nodule due to irritation and vocal
abuse.

Endoscopic view of larynx shows bilateral laryngeal nodules
on both vocal cords .

Microscopic view of benign laryngeal polyp also called (singer nodule)
showing loose fibrous stroma covered by normal squamous epithelium .

Laryngeal papilloma :
( squamous papilloma )
A benign neoplasm usually on true vocal cord that forms a
single nodule soft raspberry-like excrescence rarely more
than 1 cm. in diameter .
Histologically : Shows multiple slender finger-like
projections supported by fibrovascular core & covered by
stratified squamous epithelial cells .
In children multiple papillomatous lesions seen it tends to
recur after excision.

Endoscopic view of multiple laryngeal papillomatosis (arrows) involving
vocal cords & the surrounding laryngeal tissue .

These lesions are caused by Human papilloma virus
(HPV) type 6 & 11 .. It does not become malignant &
regresses after puberty .
Probably it is a vertical transmission from an
infected mother during delivery .
Therefore recent availability of a HPV vaccine that
could protect women during the reproductive age
group against type 6 & 11 provide a unique
apportunity for prevention of recurrent respiratory
papillomatosis (RRP) in children .

Carcinoma of the larynx :
Constitutes only 2% of all cancers .
Most common after the age of 40 years , more common in
men than women in a ratio of 7:1
Nearly all cases are smokers , alcoholics & may result from
asbestos exposure being the role .
95% are squamous cell carcinoma , rarely adenocarcinoma .
It develops directly on true vocal cord i.e glottic tumors
constituting 60%-75%, supraglottic tumors are 25%-40%.
While subglottic tumors constitute 5% only .

Human papilloma virus sequences have been
detected in a minority of cases .
Squamous cell carcinoma of the larynx begins
as a pearly gray wrinkled plaques on the
mucosal surface , ultimately ulcerates &
fungates .
The glottic tumors are generally keratinizing
squamous cell carcinoma The adjacent
mucosa show dysplasia & carcinoma in situ
changes.

Gross appearance of invasive supra-glottic squamous cell carcinoma of
the larynx .

Microscopic view of well-differentiated squamous cell
carcinoma .

Clinically :
Hoarseness of voice is the earliest symptom for
glottic cancer .
90% of glottic tumors are confined to the larynx at
the time of diagnosis
Spread beyond the larynx is uncommon because of
the sparse lymphatic supply .
Subglottic cancers are clinically silent and present
in advanced disease .

The following are prognostic and predictive factors for laryngeal
cancer.
Stage
The stage of laryngeal cancer includes the size of the tumour and how far it has grown into
other tissues around the larynx. An earlier stage cancer has a better prognosis than one
that is diagnosed at a later stage.
Location of the tumour
Cancer that starts in the glottis has a better prognosis than if the cancer starts elsewhere
in the larynx.
Spread to the lymph nodes
Cancer ha ha n pread o he l mph node in he neck ha a be er
prognosis than cancer that has spread to the lymph nodes.
The prognosis is better if the lymph nodes with the cancer are small and if
the cancer has spread to lymph nodes on only one side of the neck.

Depth of tumour growth
Tumours that grow inward and deeper into the tissues of the
larynx have a poorer prognosis than tumours that grow along
the surface of the larynx.
general health
Your general health including your performance status, your
nutritional status, how well your lungs function and other
health problems has an effect on how well you will cope
with treatment for cancer of the larynx.

Rs pathology 02

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