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part III

OBJECTIVES:

By the end of these series of lecture on respiratory system pathology the students
would be able to:
1- define the pathogenesis and the pathological features of the most common tumor
like and tumor (benign and malignant) conditions of the upper respiratory tract
including: allergic nasal polyp, angiofibroma, nasopharyngeal carcinoma, laryngeal
tumors including: vocal cord nodule, laryngeal papilloma and laryngeal carcinoma.
2- describe atelectasis of the lung and its classification.
3- define adult respiratory distress syndrome and its causes and pathological features.
4- define (the pathogenesis and the pathological features) and list obstructive
pulmonary disease: asthma, emphysema, chronic bronchitis and broncheactasis.
5- describe the pathogenesis, types and pathological features of  diffuse interstitial
lung diseases.
6- define and list the granulomatous lung diseases.
7- identify the pathogenesis and pathological features of  pulmonary infections.
8- outline the pathogenesis and the pathological features of pulmonary tuberculosis.
9- list and classify the most important lung tumors describing the pathogenesis and
pathological features, with clinical presentations including paraneoplastic syndrome
descriptions.
10- define diseases of the pluera and list the most common neoplasms of the pleura.

Tuberculosis

Tuberculosis is by far the most important of the chronic penumonia; it causes 6%
of all deaths worldwide. Tuberculosis is

"a communicable chronic granulomatous

disease caused by Mycobacterium tuberculosis".

It usually involves the lungs but

may affect any organ or tissue. Tuberculosis thrives wherever there is poverty,
crowding, and chronic debilitating illness; elderly, with their weakened defenses,
are also susceptible.

Certain disease states also increase the risk:

1. Diabetes mellitus

2. Hodgkin lymphoma

3. Chronic lung disease (particularly silicosis)

4. Chronic renal failure

5. Malnutrition & Alcoholism

6. Immunosuppression including HIV infection.



Most of these predisposing conditions are related to

impairment of T cell-mediated immunity against the
Mycobacteria.



The latter are slender rods that are acid fast, thus stained
positively with ZN stain. M. tuberculosis hominis is responsible
for most cases of tuberculosis.



Oropharyngeal  and  intestinal  tuberculosis  contracted  by
drinking  milk contaminated  with  Mycobacterium bovis is  now
rare in developed nations.



Other mycobacteria, particularly

M. avium-intracellulare,

are

much less virulent than M. tuberculosis and rarely cause
disease. However, it

complicates up to 30% of patients with

AIDS.

Pathogenesis

Primary TB



In the previously unexposed immunocompetent individual

, the source of the

organism is

exogenous

; this leads to the development of cell mediated

immunity; primarily mediated by

1 cells,

which stimulate macrophages to

kill bacteria but this is associated simultaneously with the development of

destructive tissue hypersensitivity in the form of caseation necrosis.



The virulent organisms once inside macrophages impair effective
phagolysosomal digestion, which in turn leads to

unrestricted mycobacterial

proliferation

. Thus, the

earliest phase of primary tuberculosis is characterized

by bacillary proliferation within alveolar macrophages, with resulting
bacteremia and seeding of multiple sites

Nevertheless, most persons at this

stage are asymptomatic; only about 5% of the infected develop significant
disease.



The activated macrophages release a variety of mediators including secretion
of

TNF

, which is responsible for recruitment of monocytes, which in turn

undergo activation and differentiation into the

"epithelioid histiocytes" that

characterize the granulomatous response.



About

3 weeks

are needed for the development of the

hypersensitivity reaction

Pathological features of primary TB



The inhaled bacilli are embedded in the distal airspaces of the lower part of
the upper lobe or the upper part of the lower lobe, usually close to the pleura.



As sensitization develops, a

bout1 cm area of gray-white inflammatory

consolidation develops (the Ghon focus). The center of this focus undergoes
caseous necrosis.



Tubercle bacilli, either free or within phagocytes, drain to the regional nodes,
which also often caseate.

This combination of Ghon focus and nodal

involvement is referred to as the Ghon complex



During the first few weeks, there is also lymphatic and hematogenous
dissemination to other parts of the body.



In approximately

95%

of cases, development of cell-mediated immunity

controls the infection. Hence,

the Ghon complex undergoes progressive

fibrosis, often followed by radiologically detectable calcification, and, despite
seeding of other organs, no lesions develop.

Microscopically,



there is the characteristic granulomatous
inflammatory reaction that forms both caseating
and noncaseating tubercles.



Individual tubercles are microscopic; it is only
when multiple granulomas coalesce that they
become macroscopically visible.



The granulomas are usually enclosed within a
fibroblastic rim with lymphocytes.



Multinucleate giant cells are present in the
granulomas.

A characteristic tubercle at low magnification (A) and
in detail (B) illustrates central granular caseation
(right) that is surrounded by epithelioid and
multinucleated giant cells (left). This is the usual
response seen in individuals who have developed cell-
mediated immunity to the organism. C, Occasionally,
even in immunocompetent individuals, tubercular
granulomas may not show central caseation; hence,
irrespective of the presence or absence of caseous
necrosis, special stains for acid-fast organisms must
be performed when granulomas are present in
histologic sections.

The morphologic spectrum of tuberculosis

Multiple noncaseating epithelioid granuloma of TB

Note that the granulomas are enclosed within a fibroblastic rim with lymphocytes.

Microscopically, caseous necrosis is characterized by acellular pink areas of necrosis, as seen here at
the upper right, surrounded by a granulomatous inflammatory process.

Caseating epithelioid granuloma of TB

Mycobacterium tuberculosis: acid-fast stain

Note the red rods--hence the terminology acid fast bacilli (AFB)

In immunosuppressed individuals, tuberculosis may not elicit a granulomatous response ("nonreactive
tuberculosis"); instead, sheets of foamy histiocytes are seen, packed with mycobacteria that are
demonstrable with acid-fast stains.

Mycobacterium tuberculosis: acid-fast stain

The chief potential harmful outcomes of primary
tuberculosis are

1. Induction of destructive tissue hypersensitivity, which is more damaging on
subsequent infection

(secondary TB)

2. Healed foci of scarring may harbor viable bacilli for years, and thus be a

potential nidus for reactivation

when host defenses are compromised

3. The disease progresses relentlessly into

progressive primary tuberculosis

(uncommon). This occurs in

immunocompromised individuals e.g. AIDS

patients or in those with nonspecific impairment of host defenses
(malnourished children or elderly).

Immunosuppression results in the

absence of a tissue hypersensitivity reactio

n and thus there are no granulomas

but only sheets of foamy histiocytes packed with the bacilli

(nonreactive

tuberculosis).

Progressive primary tuberculosis often resembles acute bacterial pneumonia,
with lower and middle lobe consolidation, hilar lymphadenopathy, and
pleural effusion; cavitation is rare.

Lympho-hematogenous dissemination

may

result in the development of

tuberculous meningitis and miliary tuberculosis.

Secondary Tuberculosis (Postprimary) (Reactivation Tuberculosis)

previously sensitized host.

Pathogenesis



Reactivation  of  the  dormant  primary  infection  (as  in  nonendemic,  low-
prevalence  areas)  or  re-exposure  to  the  bacilli  in  a  previously  sensitized  host
(as  in  endemic  areas)  results  in  rapid  recruitment  of  defensive  reactions  but
also  tissue  necrosis  (caseation).  This  occurs  when  the  protection  (immunity)
offered by the primary infection is weakened.



only less than 5% with primary disease subsequently develop secondary
tuberculosis.



Secondary pulmonary tuberculosis is classically localized to the apex of one or
both upper lobes. This may relate to high oxygen tension in the apices



Because of the preexistence of hypersensitivity, the bacilli excite a marked
tissue response that tends to wall off the focus.

As a result of this localization,

the regional lymph nodes involvement is less prominent than they are in
primary tuberculosis.



Cavitation occurs readily in the secondary form

, & is almost inevitable in

neglected cases. As a result erosion of airways occurs; this converts the patient
into a source of infection to others; he now raises sputum containing bacilli.

Gross features of secondary TB



The initial lesion is usually a small focus of consolidation,
less  than  2  cm  in  diameter,  near  the  apical  pleura.  Such
foci  are  sharply  circumscribed,  firm,  and  gray-white  to
yellow  areas  that  have  a  variable  amount  of  central
caseation  and  peripheral  fibrosis.  This,  if  neglected
progresses to cavitations.

Microscopic features



The active lesions show characteristic coalescent tubercles
with central caseation. TB bacilli can be demonstrated by
specific staining methods.

The upper parts of both lungs show multiple areas of softening and cavitation (arrows)

Secondary pulmonary tuberculosis

Progression of secondary TB

In favorable cases, the initial localized apical parenchymal damage undergoes
progressive healing by fibrosis & eventually represented by fibrocalcific scars.
This  happy  outcome  occurs  either  spontaneously  or  after  therapy.
Alternatively,  the  disease  may  progress  and  extend  along  several  different
pathways:

A. Progressive pulmonary tuberculosis:

the apical lesion enlarges with

expansion  of  the  area  of  caseation.  Erosion  into  a  bronchus  evacuates  the
caseous  center,  creating  a  ragged,  irregular  cavity  lined  by  caseous  material  ;
whereas  erosion  of  blood  vessels  results  in  hemoptysis.  The  pleural  cavity  is
always involved and serous pleural effusions, tuberculous empyema, or fibrous
obliteration may develop.

B. Miliary pulmonary disease

occurs when organisms drain through lymphatics

into the lymphatic ducts, which empty into the venous return to the right side
of the heart and thence into the pulmonary arteries. Individual lesions are
either microscopic or small (2-mm) foci of yellow-white; these scatter diffusely
through the lungs (miliary is derived from the resemblance of these foci to millet
seeds).

Miliary lesions may expand and coalesce to yield almost total

consolidation of large regions or even whole lobes of the lung.

Lt. multitude of small (2 to 4 mm), yellow-white foci ; these scatter diffusely through the lungs. The
miliary pattern gets its name from the resemblance of the granulomas to millet seeds.

Rt. A zoom in appearance; the miliary pattern is seen throughout the lung.

Miliary pulmonary TB

C. Endobronchial, endotracheal,

and laryngeal tuberculosis may develop

when infective material is spread either through lymphatic channels or from
expectorated infectious material. The mucosal lining may be studded with
minute granulomatous lesions.

D. Systemic miliary tuberculosis

occurs when infective foci in the lungs

invade  the  pulmonary  venous  return  to  the  heart;  the  organisms
subsequently disseminate through the systemic arterial system. Almost every
organ  in  the  body  may  be  seeded.  The  appearances  are  similar  to  miliary
pulmonary disease. Miliary tuberculosis is most prominent in the liver, bone
marrow,  spleen  ,  adrenals,  meninges,  kidneys,  fallopian  tubes,  and
epididymis.

E. Isolated-organ tuberculosis

may appear in any one of the organs or tissues

seeded

hematogenously

and may be the presenting manifestation of

tuberculosis. Organs typically involved include the

meninges (tuberculous

meningitis), kidneys (renal tuberculosis), adrenals (formerly an important
cause of Addison disease), bones (tuberculous osteomyelitis), and fallopian
tubes (tuberculous salpingitis).

When the vertebrae are affected, the disease

is referred to as

Pott disease

. Paraspinal "cold" abscesses in persons with

this disorder may track along the tissue planes to present as an abdominal
or pelvic mass.

The cut surface shows numerous gray-white granulomas.

Miliary tuberculosis of the spleen

F. Tuberculous Lymphadenitis

is the most frequent form of

extrapulmonary tuberculosis, usually occurring in the cervical
region ("scrofula"). It tends to be unifocal, and most individuals
do not have evidence of ongoing extranodal disease.

H. Intestinal tuberculosis

was fairly common as a primary focus

of tuberculosis contracted by the drinking of contaminated milk.
In developed countries today, intestinal tuberculosis is more
often a

complication of protracted advanced secondary

tuberculosis,

secondary to the swallowing of coughed-up

infective material. Typically, the organisms are trapped in

mucosal lymphoid aggregates of the small and large bowel,

which then undergo inflammatory enlargement with ulceration
of the overlying mucosa,

particularly in the ileum.

The diagnosis of pulmonary disease

is based in part on the

history and on physical and radiographic findings of consolidation or
cavitation in the apices of the lungs. However,

tubercle bacilli must be

identified to establish the diagnosis.

The most common method for diagnosis of tuberculosis remains

demonstration of acid-fast organisms in sputum by special stains e.g. acid-
fast stain

; most protocols require at least two sputum examinations before

labeling the case as sputum negative.



Conventional cultures for mycobacteria require up to 10 weeks.



PCR amplification

of M. tuberculosis DNA allows for even greater rapidity

of diagnosis and is currently approved for use. PCR assays can detect as
few as 10 organisms in clinical specimens, compared with greater than
10,000 organisms required for smear positivity. However, culture remains
the gold standard because it also allows testing of drug susceptibility.

Prognosis

is generally favorable if infections are localized to the lungs,

but it worsens significantly when the disease occurs in the setting of

aged,

debilitated, or immunosuppressed persons, who are at high risk for
developing miliary tuberculosis, and in those with multi-drug resistant-TB.
Amyloidosis may appear in persistent cases.

Nontuberculous Mycobacterial Disease



is mostly in the form of chronic but clinically localized
pulmonary disease in immunocompetent individuals.



Strains implicated most frequently include M. avium-
intracellulare.



Nontuberculous  mycobacteriosis  may  present  as  upper
lobe cavitary disease, mimicking tuberculosis, especially in
individuals  with  a  long-standing  history  of  smoking  or
alcoholism.



The presence of concomitant chronic pulmonary disease
e.g. COPD, is an important risk factor.



In immunosuppressed individuals (primarily, HIV-positive
patients), M. avium-intracellulare presents as disseminated
disease, associated with systemic symptoms.

LUNG TUMORS

Bronchial carcinomas

constitute

95%

of primary lung

tumors; the remaining

includes

bronchial carcinoids,

sarcomas, lymphomas

, and a few benign lesions.

Pulmonary Hamartoma



is the most common benign lesion;



it is rounded



small (3-4 cm)



discrete mass that often displayed as "coin" lesion on chest
radiographs.



They consist mainly of mature cartilage with a scattered of
bronchial glands that are often admixed with fat, fibrous
tissue, and blood vessels in varying proportions.

Here are two examples of a benign lung neoplasm known as a pulmonary hamartoma. These
uncommon lesions appear on chest radiograph as a "coin lesion" that has a differential diagnosis of
granuloma and localized malignant neoplasm. They are firm and discreet and often have calcifications
in them that also appear on radiography. Most are small (less than 2 cm).

Pulmonary hamartoma

The pulmonary hamartoma is seen microscopically to be composed mostly of benign cartilage

on the right that is jumbled with a fibrovascular stroma and scattered bronchial glands on the

left. A hamartoma is a neoplasm in an organ that is composed of tissue elements normally found

at that site, but growing in a haphazard mass.

Pulmonary hamartoma

Carcinomas



Carcinoma of the lung is the commonest cause of cancer-
related deaths in industrialized countries.



The rate of increase among males is slowing down, but it
continues to accelerate among females; it has overrun breast
cancer as a cause of death since 1987.



This is undoubtedly related to the strong relationship of

cigarette smoking and lung cancer.



Most patients are in the age group of

50-60 years.



The prognosis of lung cancer is very poor: the 5-year survival
rate for all stages combined is about 15%.

Squamous cell carcinoma ( 25-40%).

Adenocarcinoma (25-40%)

Small cell carcinoma (20-25%)

Large cell carcinoma (10-15%)

There are four major histologic types of lung carcinomas

1. Squamous cell carcinoma
2. Adenocarcinoma
3. Small-cell carcinoma
4. Large-cell carcinoma.



Adenocarcinomas are the most common primary tumors arising in women,
in lifetime nonsmokers, and in persons younger than 45 years.



For therapeutic purposes, carcinomas of the lung are divided into two groups:

small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC).

The

latter category includes

squamous cell, adenocarcinomas, and large-cell

carcinomas.



The reason for this division is that virtually

all SCLCs have metastasized by

the time of diagnosis

and hence are

not curable by surgery

. Therefore, they

are best treated by

chemotherapy, with or without radiation.



NSCLCs usually respond poorly to chemotherapy and are better treated by
surgery.



These two groups show genetic differences.



SCLCs are characterized by a high frequency of

RB gene mutations

, while

the

p16 gene

is commonly inactivated in NSCLCs.

Etiology and Pathogenesis



It seems that large areas of the respiratory mucosa have undergone

mutation after exposure to carcinogens

("field effect").



On this fertile soil, those cells that accumulate additional mutations

ultimately develop into cancer.

The role of Cigarette smoking



is the main agent responsible for the genetic changes that give rise to lung
cancers.



About

90%

of lung cancers occur in active smokers (or those who stopped

recently).



The increased risk is

60 times

greater among habitual heavy smokers (two

packs a day for 20 years) compared with nonsmokers.



Women have a higher susceptibility to carcinogens in tobacco than men.



Although cessation of smoking decreases the risk of developing lung cancer
over time, genetic changes that predate lung cancer can persist for many
years in the bronchial epithelium of ex-smokers.



Passive smoking

(proximity to cigarette smokers)

increases the risk to twice that of nonsmokers.



There is a linear correlation between the intensity
of smoking and the appearance of squamous
metaplasia that progresses to squamous dysplasia
and carcinoma in situ,

before culminating in

invasive cancer.



Squamous and small-cell carcinomas show the
strongest association with tobacco exposure.

The role of occupation-related environmental agents;



These may act

alone

synergistically

with smoking to be

pathogenitically related to some lung cancers, for e.g.

radioactive ores;

dusts containing arsenic, chromium, uranium, nickel, vinyl chloride, and
mustard gas.



Exposure to

asbestos increases the risk of lung cancer 5 times in

nonsmokers.

However, heavy smoking with asbestos exposure increases

the risk to

50 times.

The role of hereditary (genetic) factors



not all persons exposed to tobacco smoke develop cancer.



It seems that the effect of carcinogens is modulated by hereditary
(genetic) factors.



Many procarcinogens require metabolic activation via the

P-450 enzyme

system for conversion into carcinogens.



Evidences  support  this  scenario  in  that  persons  with  specific  genetic
abnormalities  of  P-450  genes  have  an  increased  capacity  to  metabolize
procarcinogens  derived  from  cigarette  smoke  and  thus  sustain  the
greatest risk of developing lung cancer.

The role of bronchioalveolar stem cells (BASCs) in
the development of peripheral adenocarcinoma:



the

"cell of origin"

for peripheral adenocarcinomas is the

BASCs.



Following peripheral lung injury, the multipotent BASCs
undergo  expansion  to  replenish  the  normal  cell  types
found  in  this  location,  thereby  facilitating  epithelial
regeneration.



BASCs are considered the tumor initiating cells i.e. the
first to acquire the somatic

K-RAS mutation

that enables

their daughter cells to

escape normal "checkpoint"

mechanisms and result in pulmonary adenocarcinomas.

Gross Features



Carcinomas of the lung begin as small mucosal lesions that are usually firm
and  gray-white.  Further  enlargement  result  in  either  intraluminal  masses,
or  invasion  of  the  bronchial  wall  to  form  large  bulky  masses  pushing  into
adjacent  lung  parenchyma.

Obstruction of the bronchial lumen often

produces distal atelectasis and infection.



Some tumors tend to a

rise centrally near the hilum

i.e. in major brochi,

these are exemplified by

squamous cell & small cell carcinomas



Adenocarcinomas

may occur

centrally but are usually more peripherally

located,

many arising in relation to peripheral lung scars

("scar

carcinomas").



Large tumors may undergo cavitation; this is caused by central necrosis.



These tumors may extend to the pleura, invade the pleural cavity and chest
wall, and spread to adjacent intrathoracic structures.



Metastasis occurs first to

peribronchial, hilar and mediastinal lymph nodes



More distant spread can occur via the

lymphatics or the hematogenous

route.

Squamous cell carcinoma: Note whitish endobronchial obstructive mass.

Early bronchial carcinoma

This is a fairly small carcinoma which has arisen in a bronchus blue (arrow), and then invaded into
surrounding lung tissue; tumor obstructing bronchus

Early bronchial carcinoma

The tumor usually begin as central (hilar) masses and grow contiguously into the peripheral

parenchyma and adjacent pleura

Squamous cell carcinomas

This is a large squamous cell carcinoma in
which a portion of the tumor demonstrates
central cavitation (arrow), probably because
the tumor outgrew its blood supply.

Squamous cell carcinoma showing large central area of necrosis and cystic change.

Squamous cell carcinoma

This pale white tumor is obstructing the right main
bronchus. a squamous cell carcinoma of the lung that is
arising centrally in the lung (as most squamous cell
carcinomas do). Microscopy shows squamous cell
carcinoma.

Microscopic features

Squamous cell carcinomas



are often preceded for years by

squamous metaplasia

or dysplasia in the bronchial epithelium

, which then

transforms to

carcinoma in situ,

a phase that may last

for several years.



These tumors range from

well-differentiated showing

keratin pearls and intercellular bridges to poorly
differentiated neoplasms having only minimal
residual squamous cell features.

Above: nests of squamous cells with keratin

production (arrow).

Below: the pink cytoplasm with distinct cell
borders and intercellular bridges
characteristic for a squamous cell
carcinoma are seen here at high
magnification. Such features are seen in
well-differentiated tumors (those that more
closely mimic the cell of origin).

Adenocarcinomas



assume a variety of forms, including

gland

forming (acinar), papillary, and solid types.



The solid variant often requires demonstration
of

intracellular mucin

production by special

stains to establish its adenocarcinomatous
nature.

Rt. This chest radiograph demonstrates a large 5 cm diameter adenocarcinoma of the right lower lobe.

The bright opacity in the middle of the mass is a calcified granuloma.

Lt. Adenocarcinoma: Peripheral mass located immediately under visceral pleura, with pleural

retraction.

Adenocarcinoma. The tumor is peripherally located and
has extended to the pleura.

Peripheral carcinoma

Malignant epithelial cells forming glandular
structures with mucin secretion.

Pulmonary adenocarcinoma

papillary and micropapillary structures

Bronchioloalveolar carcinomas (BACs)



are a subtype of adenocarcinomas.



They involve

peripheral parts of the lung, either as a

single nodule or, more often, as multiple diffuse
nodules that may coalesce to produce pneumonia-
like consolidation.



The key feature of BACs is their growth

along

preexisting structures and preservation of alveolar
architecture.

Greyish-white tumor involves 2/3 of left upper lobe and
1/3 of the lower lobe. The color and distribution suggest
pneumonic consolidation. Secondary tumors can
peoduce the same appearance.

The tumor is composed of columnar cells
that proliferate along the framework of
alveolar septae. The cells are well-
differentiated.

Large-cell carcinomas



undifferentiated malignant epithelial tumors that lack
the cytologic features of glandular or squamous
differentiation



The cells have large nuclei, prominent nucleoli.



Large-cell

carcinomas

probably

represent

undifferentiated examples of squamous cell or
adenocarcinomas at the light microscopic level.



Ultrastructurally, however, minimal glandular or
squamous differentiation is common.

Undifferentiated large cell carcinoma. Tumor is formed by large cells growing in solid nests without
evidence of glandular or squamous differentiation.

Small-cell lung carcinomas



are  composed  of  small  tumor  cells  with  a  round  to
fusiform  nuclei  with  finely  granular  chromatin,  and
scant cytoplasm.



Mitotic

figures are frequently seen.



Despite the term of

"small,"

the neoplastic cells are

usually

twice the size of resting lymphocytes.



Necrosis

is invariably present and may be extensive.



These tumors are derived from

neuroendocrine cells

of the lung, and hence they express a variety of
neuroendocrine markers in addition to many
polypeptide

hormones

that

may

result

paraneoplastic syndromes.

Arising centrally in this lung and spreading

extensively is a small cell anaplastic (oat cell)

carcinoma. The cut surface of this tumor has a

soft, lobulated, white to tan appearance. The

tumor seen here has caused obstruction of the

main bronchus to left lung so that the distal

lung is collapsed. Oat cell carcinomas are very

aggressive and often metastasize widely before

the primary tumor mass in the lung reaches a

large size.

The tumor is composed of small cells with darkly

staining oval to spindle nuclei and extremely scanty

cytoplasm.

Combined tumors:

a  minority  of  bronchogenic  carcinomas  reveal
more  than  one  line  of  differentiation,  sometimes
several,  suggesting  that  all  are  derived  from  a
multipotential progenitor cell.



All subtypes of lung cancer show involvement of successive
chains of nodes about the

carina, in the mediastinum, and

in the neck (scalene nodes) and clavicular regions and,
sooner or later, distant metastases.



Involvement of the

left supraclavicular node (Virchow node)

is particularly characteristic and sometimes calls attention
to an occult primary tumor.



These cancers, when advanced, often extend into the

pericardial or pleural spaces, leading to inflammation and
effusions.



They may compress or infiltrate the superior vena cava to
cause either venous congestion or the full-blown

vena caval

syndrome.



Apical neoplasms

may invade the brachial or cervical

sympathetic plexus to cause severe pain in the distribution
of the ulnar nerve or to produce

Horner syndrome

(ipsilateral enophthalmos, ptosis, miosis, and anhidrosis).



Such apical neoplasms are sometimes called

Pancoast

tumors,

and the combination of clinical findings is known as

Pancoast syndrome.



Pancoast tumor is often accompanied by destruction of the
first and second ribs and sometimes thoracic vertebrae.



As with other cancers, tumor-node-metastasis (TNM)
categories have been established to indicate the size and
spread of the primary neoplasm.

Course & prognosis



Carcinomas of the lung are silent lesions that more often than not have
spread beyond curable resection at the time of diagnosis.



Too  often,  the  tumor  presents  with  symptoms  related  to  metastatic
spread  to  the  brain  (mental  or  neurologic  changes),  liver
(hepatomegaly), or bones (pain).



Overall, NSCLCs have a better prognosis than SCLCs.



NSCLCs

(squamous cell carcinomas or adenocarcinomas) are

detected before metastasis or local spread, cure is possible by
lobectomy or pneumonectomy.



SCLCs

, on the other hand, is almost always have spread by the time of

the diagnosis, even if the primary tumor appears small and localized.



Thus, surgical resection is not a practical treatment. They are very
sensitive to chemotherapy but invariably recur. Median survival even
with treatment is 1 year.

Paraneoplastic syndromes

Up to

10%

of all patients with lung cancer develop clinically overt

paraneoplastic syndromes. These include

1. Hypercalcemia

caused by secretion of a parathyroid hormone-related

peptide.

2. Cushing syndrome

(from increased production of ACTH);

3. Inappropriate secretion of ADH

4. Neuromuscular syndromes,

including a myasthenic syndrome,

peripheral neuropathy, and polymyositis

5. Clubbing of the fingers and hypertrophic pulmonary
osteoarthropathy

6. Hematologic manifestations,

including migratory thrombophlebitis,

nonbacterial endocarditis, and disseminated intravascular coagulation.

Hypercalcemia is most often encountered with squamous cell carcinomas, the
hematologic syndromes with adenocarcinomas. The remaining syndromes are
much more common with small-cell neoplasms, but exceptions occur.

Bronchial Carcinoids



are thought to arise from the

Kulchitsky cells

(neuroendocrine cells) of the

bronchial mucosa and represent about

5% of all pulmonary neoplasms.



The mean age of occurrence is

40 years.



Ultrastructurally,

the neoplastic cells contain cytoplasmic dense-core

neurosecretory granules and may secrete hormonally active polypeptides.
In contrast to the more ominous small-cell carcinomas, carcinoids are often
resectable and curable.

Gross features

Most bronchial carcinoids originate in main bronchi and grow in one of two
patterns

1. An Obstructing spherical, intraluminal mass

2. A mucosal plaque penetrating the bronchial wall to fan out in the peribronchial
tissue.

Some tumors, (about 10%) metastasize to hilar nodes but distant metastasis is
rare.

Microscopic features



They are composed of nests of uniform cells that have regular round
nuclei with

"salt-and pepper"

chromatin, absent or rare mitoses



A subset designated atypical carcinoid that differ from the typical by

1. Having higher mitotic rate, cytologic pleomorphism , and focal necrosis

2. Having a higher incidence of lymph node and distant metastasis.

Typical  carcinoid,  atypical  carcinoid,  and  small-cell
carcinoma  can  be  considered  to  represent  a  continuum
of  increasing  histologic  aggressiveness  and  malignant
potential

within

the

spectrum

pulmonary

neuroendocrine neoplasms.

A, Bronchial Carcinoid Tumor: Yellow intrabronchial mass (lower) has resulted in obstructive
bronchiectasis

B, Histologic appearance demonstrating trabecular arrangement of small, rounded, uniform cells.

Bronchial carcinoid

Whole mount of carcinoid tumor showing polypoid endobronchial growth.

The tumor is composed of nests of uniform cells that have regular round nuclei & absent or rare
mitoses

There is typical nesting of marked
pleomorphic cells. mitotic activity, and
necrosis are also present elsewhere.

Course & prognosis



Most clinical features are related to their intraluminal
growth (cough, hemoptysis, and recurrent bronchial and
pulmonary infections).



Some are asymptomatic and discovered by chance on
imaging studies. Only rarely do they induce the

carcinoid syndrome,

characterized by intermittent

attacks of diarrhea, flushing, and cyanosis.



The reported

10-year

survival rates for typical

carcinoids are

85%

, but these drop to

35%

for atypical

carcinoids.



Only 5% of patients with SCLC are alive at 10 years.

THE PLEURA

Pleural Effusion

refers to the presence of fluid in the pleural space. The fluid

can be either a transudate or an exudate. A transudate is termed

hydrothorax

, which

is mostly due to CHF. An exudates is characterized by protein content of 3.0 gm/dl
or more and, often, inflammatory cells. The four

principal causes of pleural

exudate are

1. Microbial invasion; either direct extension of a pulmonary infection or blood-
borne seeding (suppurative exudates or empyema)

2. Cancer (lung carcinoma, metastatic cancers to the lung or pleural
mesothelioma

3. Pulmonary infarction

4. Viral pleuritis

Less common causes include SLE, rheumatoid arthritis, uremia.

Cancer should be suspected as the underlying cause of an exudative effusion in
any  patient  older  than  the  age  of  40,  particularly  when  there  is  no  febrile
illness,  no  pain,  and  a  negative  tuberculin  test  result.  These  effusions
characteristically  are  large  and  frequently  bloody  (hemorrhagic).  Cytologic
examination may reveal malignant and inflammatory cells.

Pneumothorax

refers to air in the pleural sac. It may occur in young,

healthy adults, usually men without any known pulmonary disease

(spontaneous pneumothorax),

or as a result of some thoracic (e.g. a fractured

rib) or lung disorder (secondary pneumothorax).

Secondary pneumothorax

occurs with rupture of any pulmonary lesion

situated close to the pleural surface that allows inspired air to gain access to the
pleural cavity. Such pulmonary lesions include

emphysema, lung abscess,

tuberculosis, carcinoma, etc. Supportive mechanical ventilation with high
pressure may also trigger secondary pneumothorax.

A serious complication may occur through a ball-valve leak that creates a

tension pneumothorax.

This shifts the mediastinum, which may be

followed by impairment of the pulmonary circulation that may be fatal.

With prolonged collapse, the lung becomes vulnerable to infection, as does the
pleural cavity.

Empyema

thus

important

complication

pneumothorax

(pyopneumothorax).

Hemothorax

is the collection of whole blood (in contrast to

bloody effusion) in the pleural cavity, is a complication of a
ruptured intrathoracic aortic aneurysm that is almost always
fatal.

Chylothorax

is a pleural collection of a milky lymphatic

fluid containing microglobules of lipid. It implies obstruction
of the major lymph ducts, usually by an intrathoracic cancer
(e.g., a primary or secondary mediastinal neoplasm, such as
a lymphoma).

Malignant Mesothelioma



is a rare cancer of mesothelial cells, usually arising in the
parietal or visceral pleura.



It also occurs, much less commonly, in the peritoneum and
pericardium.



In the USA approximately 50% of individuals with this
cancer have a history of exposure to

asbestos.



The latent period for developing malignant mesotheliomas
is long

(25 to 40 years)

after initial asbestos exposure.



The  combination  of  cigarette  smoking  and  asbestos
exposure  greatly  increases  the  risk  of  bronchogenic
carcinoma, but it does  not increase the risk of developing
malignant mesotheliomas.

Gross features



These tumors begin in a localized area but in the
course of time spread widely.



At  autopsy,  the  affected  lung  is  typically
ensheathed  by  a  yellow-white,  firm  layer  of  tumor
that obliterates the pleural space



The neoplasm may directly invade the thoracic
wall or the subpleural lung tissue.

M/67. This vertical slice of the right lung shows the
manner in which a pleural mesothelioma causes
thickening of the pleura and encases the whole
lung and mediastinum.

Malignant mesothelioma pleura