Pathology Review

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Pathology Review ...

Pathology Review

    January 31, 2002

    Dr. Kirshenbaum

Note to readers: wow, I can’t believe I just finished typing this whole thing ? First of

    all, I’d like to thank Michelle H. for taking care of my tape while I was gone. Also I’d

    like to thank Bijal and Mili for their notes. I couldn’t have done it w/o you, guys, thanks!

    I just wanted to mention that the first part of this coop (lung) comes mainly from my notes,

    Robbins, and some CPP lectures. The rest of it comes from the tape, Mili and Bijal’s

    notes, and Robbins. Enjoy! (you might need a cup of coffee)


    Bone and Joints

    Soft Tissue Tumors

First things first….a little bit of normal anatomy and physiology of the lung……………

Right lung has 3 lobes, whereas left lung has 2 lobes and a lingula which takes place of a

    third lobe. Please note that upper lobes are more anterior than lower lobes (which are more posterior). Right main stem bronchus is much more vertical than left main stem

    bronchus, and therefore if there is aspiration, it is likely to go into the right lung. The

    following is the normal order of respiratory structures:

Trachea ? primary bronchi ? secondary bronchi ? tertiary bronchi, etc. ? bronchioles

    (diameter is < 2mm) ? terminal bronchioles ? respiratory bronchioles

    alveolar ducts alveolar sacs alveoli. The latter highlighted structures make up the acinus. The concept of acinus is particularly important when we discuss different

    types of emphysema (more on this later). A lobule consists of 3-5 terminal bronchioles and all of their branches. As we move from trachea down to bronchioles, we lose

    cartilage and gain smooth muscle (note: there is no smooth muscle in alveoli).

Lungs have double blood supply:

    a) pulmonary artery (major)

    b) bronchial circulation from aorta (branches from aorta come off and supply mostly

    the conducting zones of the lung that do not participate in gas exchange; minor)

Therefore, since lung has double blood supply, infarcts from PE are rarely seen.

    However, in a person with CHF and a medium-sized embolus, lung is likely to be

    infarcted. This infarct will probably be hemorrhagic (vs. white) due to dual blood supply

    mentioned above and due to sponginess of the lung.

A little bit of histology (…yes, it’s coming back to haunt us again): most respiratory tract

    is covered with pseudostratified ciliated columnar epithelium. As we go distally, epithelium will change into columnar. Remember that alveoli are covered with

    pneumocytes type I (95%) and pneumocytes II (5%). They produce surfactant and

regenerate in case of injury. There is, however, an exception to “pseudostratified ciliated

    columnar epithelium” rule: vocal cords are covered with squamous epithelium. By the

    way(btw) it is very important to realize that alveolar septa comprise intersitium of the

    lung. So, the septa are composed of pneumocytes (type I and type II), BM of

    pneumocytes and endothelial cells and of endothelial cells themselves.

There are 2 functions of the lung: ventilation and gas exchange. The average tidal

    volume (TV) is 500ml (this is the amount of air we move during normal quiet breathing)

Pulmonary defense relies on mucociliary action (mucus secretion and action of cilia)

    and on work of alveolar macrophages in case the noxious agent gets as far down as


Cyanosis occurs when Hemoglobin is inadequately oxygenated. Cyanosis could be of

    pulmonary origin (i.e., impaired gas exchange or V/Q mismatch) or it could be of cardiac

    origin. It is possible to differentiate btw the two by giving a patient high concentration of

    oxygen. If the problem is of pulmonary origin, we are likely to see improvement. If,

    however, cyanosis is due to failing heart, patient will not improve

Now moving on to pathology. As always, we have several categories of issues to talk

    about. The following is the outline I am going to follow here.

    I. Congenital diseases of the lung

    II. Atelectasis

    III. Diseases of vascular origin

    IV. Obstructive vs. Restrictive diseases

    A. Restrictive diseases of infectious origin (i.e., pneumonias)

    B. Restrictive diseases of non-infectious origin (i.e., pulmonary

    alveolar proteinosis)

     V. Tumors

    I. Congenital diseases of the lung

    Dr. K literally spent 2 min on this section:

    A. Agenesis/hypoplasia: the lung either does not form or it does not form


    B. Broncogenic cysts: these would be cystic structures lined by normal

    respiraty epithelium (pseudostratified ciliated columnar epithelium).

    These can get infected.

    C. Bronchopulmonary sequestration: this refers to presence of lung tissue

    that has no connection to the airway system. These can be intralobar

    (located inside the lung) or extralobar (located outside of the lung, i.e., in


    II. Atelectasis

    Atelectasis means collapse of the lung or incomplete expansion of the lung. There are 3

    types of acquired atelectasis

    Acquired (more on these below)

    A. Obstructive

    B. Compressive

    C. Contraction

    Atelectasis can also be congenial. Two words on this…. Atelectasis neonetorum is when alveoli never expand. The second kind of congenital

    atelectasis is seen in premature infants when they don’t secrete enough surfactant. Alveoli expand initially, but don’t stay expanded due to enormous surface tension.

Moving on to acquired atelectasis…

    Obstructive atelectasis occurs when there is total obstruction of an airway. It is usually caused to excessive secretions (i.e., found in chronic bronchitis, bronchiectasis, etc.).

    There is resorption of air distal to obstruction and subsequent collapse.

Compressive atelectasis has to with squishing of the lung from the outside (pleural

    cavity). It could be due to collection of blood, air, pus, etc. in the pleural cavity.

Contraction atelectasis results from fibrotic changes in the lung. In this situation lung

    cannot expand. Just in case you are wondering, refer back to the definition of atelectasis

    above (atelectasis is collapse or incomplete expansion of the lung).

    III. Vascular Diseases of the Lung

    A. Pulmonary congestion/edema. As we already know, there are 2 possible

    hemodynamic mechanisms, either

    a) increased hydrostatic pressure secondary to CHF or mitral

    stenosis, for ex. or

    b) decreased oncotic pressure. There are many reasons for

    decreased concentration of albumin in blood, i.e., liver cirrhosis

    and problems with synthesis, nephrotic syndrome and loss of

    protein in the urine, loss of protein in GI tract, etc.

    Pulmonary congestion could be acute or chronic. In the latter, we’ll

    probably see “heart failure” cells, which are macrophages filled with


    B. ARDS (Adult Respiratory Distress Syndrome, aka shock lung, diffuse

    alveolar damage). Dr. K mentioned that we should be familiar with all the


    Histologically, ARDS will look like IRDS (Infantile Respiratory Distress

    Syndrome). Etiologies, however, differ. Whereas IRDS results from

    insufficiency of surfactant, ARDS can be caused by

    a) shock

    b) sepsis

    c) chemicals, burns

    d) pancreatitis, etc.

    What we see in all of these cases is diffuse damage to alveoli, and

    pulmonary edema (with proteins) as a result of that. Note, that this edema

    is of non-cardiogenic origin (i.e., not from CHF). Pneumocytes necrose.

    This results in hyaline membranes covering the alveoli, which consist of

    fibrin-rich deposits and dead pneumocytes, impairing gas exchange and

    leading to a high rate of mortality. We also see regeneration of type II

    pneumocytes (remember, we mentioned before that not only do these cell

    secrete surfactant but also regenerate in case of injury)

    C. PE / Infarcts of the Lung

    Remember, the most common origin of PE is DVT. When does one

    develop thrombi, you ask? The answer lies in the good old Virchow triad

    (stasis, hypercoaguable state, i.e., cancer, surgery, antithrombin III

    deficiency, protein C or S deficiency, etc., and endothelial injury)

    Saddle embolus is one huge embolus that sits at the bifurcation of one of

    the main pulmonary arteries. Result: death. Lung doesn’t infarct since

    there is not enough time. This person will die of acute cor pulmonale.

    Infarcts are rare, but can occur with medium-sized emboli, especially if

    the person has underlying heart disease. Infarcts will be hemorrhagic.

    D. Pulmonary HTN

    Primary pulmonary HTN is extremely rare. This usually occurs in 20-30

    y.o women for unknown reason.

    Secondary pulmonary HTN can occur in any of the following

    a) intrinsic lung disease

    b) congenital or acquired disease of the heart, i.e., mitral


    c) multiple emboli plugging up vessels.

    d) sleep apnea

IV. Obstructive vs. Restrictive Diseases (this is a very important



    Obstructive diseases are characterized by increased resistance to airflow on expiration

    and therefore decreased FEV1/FVC (forced expiratory volume in 1 sec/Forced Vital


    Differential for Obstructive diseases, aka COPD:

    a) emphysema

    b) chronic bronchitis

    c) asthma

    d) bronchiectasis

Note that emphysema and chronic bronchitis often coexist (see my beautiful artwork


Chronic bronchitis is a clinical definition. Chronic bronchitis is defined by sputum

    production for 3 months for 2 consecutive years. Emphysema is a morphologic definition.

    emphysema, based on location of involvement. There are 3 subcategories of

    a) centroacinar (95%), this is the most common type and is associated with smoking.

    In this type of emphysema we see dilatation of respiratory bronchioles and sparing of

    distal alveoli.

    b) panacinar, the whole acinus is involved, from respiratory bronchioles to distal

    alveoli. This type is not frequent. You must remember that this is they type

    associated with alpha 1 anti-trypsin deficiency (autosomal dominant condition).

    c) distal acinar, obviously involves alveolar spaces. This type is associated with

    formation of subpleural blebs (collection of distal dilated alveoli), which can

    eventually rupture, causing pneumothorax. This is a common cause of pneumothorax

    in young adults.

Pathogenesis of emphysema:

Protease/antiprotease theory: There is usually a balance btw proteases, i.e., elastases

    produced by PMNs, etc., and antiproteases, i.e., alpha 1 anti-trypsin, synthesized in the

    liver. If there is imbalance, one gets emphysema. Smoking causes both increased

    amounts of proteases and suppression of antiproteases. Now we understand how

    smoking leads to emphysema. Or, one can have mutation of alpha 1 anti-trypsin protein and shift the balance towards degradation of lung interstitum by proteases. As we

    mentioned above, the person is likely to develop panacinar emphysema.

    Under the microscope, we’ll see dilated alveoli and also clubbing of alveolar septa (this was discussed in our lung lab and wasn’t elaborated on here)

    As a result of air trapping, which is due to collapse of the airways upon expiration (that’s because the bronchioles loose the alveolar septa that keep them open), lung will be

    dilated and patient will have a barrel chest (increased anterior-posterior diameter) = increased FRC. Patient is not likely to have clinical signs/symptoms until about one third

    of lung parenchyma is involved. Patient will present with expiratory wheezing and SOB.

    In pure emphysema (w/o chronic bronchitis), airways are not clogged up, patient will

    hyperventilate and remain well oxygenated, and is therefore called a pink puffer. In chronic bronchitis, there is a lot of mucus collecting if the airways, and it is difficult to

    maintain gas exchange. Therefore this person is called a blue bloater.

Chronic Bronchitis

Etiology: smoking, infections

    Histology: we’ll see increased mucus secretion, plugs, and scarring around bronchi


    In asthmatics, there is increased irritation of trachobronchial tree, NOT

    alveolar tree (superimportant) with paroxysmal narrowing of the airways. Asthma is

    usually a reversible condition. If condition gets to the state where it is no longer

    reversible, it is called status asthmaticus (obviously this is a very severe form and often leads to death).

As we learned in CPP, to diagnose asthma, one usually administers beta 2 agonist and

    looks for 12-15% improvement in FEV1/FVC ratio from baseline.

Causes of Asthma

    A. Atopic asthma. This is a hypersensitivity reaction triggered by environmental

    stimuli and mediated by IgE (type I hypersentitivity reaction). Upon IgE binding

    and cross-linking, histamine, prostaglandins, leukotrienes, and many other

    reagents are released from mast cells and other inflammatory cells. Clinically, the

    patient will present with dyspnea and congestion due to increased bronchial


    B. Nonatopic asthma. This type can be precipitated by infections, often viruses, i.e.,

    rhinovirus, parainfluenza virus.

    C. Drug-induced asthma. Some people have sensitivity to drugs such as aspirin

    These patients usually have recurrent rhinitus and nasal polyps (just as a review,

    in polyps histologically we’ll see respiratory epithelium covering stroma with

    edema and inflammatory cells). These nasal polyps are non-neoplastic.

    D. Occupational asthma. It is stimulated by fumes, dusts, gases, and other


    E. Allergic Bronchpulmonary Aspergillosis. This is caused by hypersensitivity to

    aspergillus (fungus).

Histology of asthma:

    a) occlusion of bronchi with thick mucus

    b) eosinophils because it is often an allergic reaction

    c) Curschmann spirals: mucous plugs in the bronchi will contain whorls

    of shed epithelium, which are known as Curschmann spirals

    d) Charcot-Leyden crystals, which are collections of eosinophil membrane


    e) Bronchial smooth muscle hypertrophy.


    Bronchiectasis leads to or is associated with dilated bronchioles. Grossly, we’ll see

    bronchiole structures peripherally, all the way down to pleura, where we should normally

    see spongy alveoli. Grossly, we can differentiate bronchiectasis from emphysema by the

    presence of some cartilage around the dilated airways (in emphysema obviously we

    won’t see any cartilage around the dilated alveoli).

Etiology: Bronchiectasis is associated with chronic necrotizing infections of bronchioles,

    such as seen in cystic fibrosis patients, which eventually start looking like bronchi.

    Clinically, these patients will present with fever, very productive cough (especially in the

    morning) with foul-smelling sputum. Bronchiectasis is also part of Kartagener

    syndrome (which is characterized by bronchiectasis, sinusitis, male infertility, and situs

    inversus, i.e., where all organs in the body are on the opposite side from where they are

    normally seen). In this syndrome, due to impaired ciliary action, bacteria and other

    foreign agents can’t be cleared from the lung, eventually resulting in bronchiectasis.

    RESTRICTIVE DISEASES Usually in restrictive disease we see small lungs because it is hard to blow them up.

    Restrictive diseases are either pulmonary in origin, i.e., pneumonias or extrapulmonary,

    i.e., caused by neuromuscular disease so that diaphragm can’t contract properly for ex., or by kyphosis, scoliosis, or obesity.

Here we’ll talk about two general types of restrictive diseases of pulmonary origin:


    Miscellaneous Diseases

Pulmonary Infections

    Upper respiratory tract infections (acute bronchitis, tracheolaryngobronchitis, etc.) are

    very common and are usually of viral origin. Patients usually get better spontaneously.

Lower respiratory tract infection is synonymous with pneumonia. There are different

    ways to categorize pneumonias:

Anatomical (this is what we are interested in the most)

    a) lobar

    b) interstitial

    c) bronchopneumonia


    a) staph

    b) strep, etc.

Host reaction:

    a) supprative

    b) fibrionus, etc.

Keeping anatomical categories in mind, we can further categorize pneumonias into

    Intralveolar (inside alveoli)

    Intersitial (affecting alveolar septae)

First we’ll talk about intralveolar pneumonias, which are lobar and

    bronchopneumonias. Both of these are usually due to bacterial infections. There are several important differences between these 2 pneumonias. First we’ll consider

bronchopneumonias. In bronchopneumonia, which starts in the bronchioles, there is

    patchy consolidation (solidification) of the lung, usually bilateral. It tends to occur in

    extremes of age: infancy and old age. It can be caused almost by any bacteria (staph,

    strep, gram negatives) and also by some fungi. Histologically, we’ll see necrosis, fibrin,

    and lots of PMNs.

Lobar pneumonia is, as the name implies, acute bacterial infection of the whole lobe of

    the lung, which starts in alveoli and spreads through the pores of Kohn. About 90%

    of lobar pneumonias are caused by Streptococcus pneumoniae (perhaps due to

    presence of a capsule, this bacterium tends to spread throughout the whole lobe of the

    lung before it can be contained). Unlike bronchopneumonias, lobar pneumonias can

    occur at any age.

Complications of lobar and bronchopneumonias: abcess formation, empyema (by

    extention of inflammatory process to pleura), pericarditis, bacterimia, sepsis.

Histology of both lobar and bronchopneumonias:

    There are 4 different stages. Please note that these are usually used to describe lobar

    pneumonia, b/c it tends to involve the whole lobe, and these 4 stages can be seen grossly.

    Since bronchopneumonias are usually patchy and usually don’t involve large areas of the

    lungs, these 4 stages cannot be grossly observed. However, the same 4 stages would be

    observed under the microscope for bronchopneumonia as for lobar pneumonia. Here

    they are:

    1. Congestion: vascular engorgement, edema

    2. Red hepatization (lung at this point would resemble liver): we would see

    fibrin and inflammatory cells in alveolar spaces.

    3. Gray hepatization: cells are breaking up, supprative exudates is still


    4. Resolution: eventually exudate undergoes enzymatic digestion to produce

    semifluid debri, which is then resorbed.

On physical exam, we’ll hear crackles upon auscultation. Patient will present with

    productive cough. Remember, we are talking about intralveolar pneumonias here.

    There will be junk inside the alveoli, which the patient will be coughing up.

    Now we’ll talk about intersitial pneumonias (also referred to as “walking pneumonias”). Here we’ll see inflammation of lung interstitium or alveolar septae.


    a) Viruses, such as influenza, RSV, rhinovirus, parainfluenza, measles, etc.

    b) Chlamydia

    c) Mycoplasma, can do mycoplasma serology or cold agglutinin test to diagnose

    and differentiate mycoplasma from viral pneumonia (could be asked on boards)

On physical exam, we won’t hear crackles b/c there is nothing going on inside the

    alveolar spaces. Hence, in this case, cough will be non-productive.

Still talking about infections of the lung (we just covered intraolveolar and interstitial

    pneumonias), now Dr. K. mentioned TB.

Primary TB: Ghon complex, which consists of lung parenchymal subpleural lesion and

    enlarged hilar lymph nodes with caseating granulomas. These people are usually

    asymptomatic. These findings, however, can be picked up on X-ray. Then we know that

    this patient at some point in his/her life has probably been exposed to TB.

Secondary TB: It usually results from reactivation of primary TB. Secondary TB

    usually produces more damage to the lung than primary TB does. Secondary TB can

    progress and result in fibrocaseous (cavitary) TB (when caseous lesion communicates

    with a bronchiole and is drained, resulting in a cavity). It can also spread

    lymphohematogenously (lung is heavily supplied by blood and lymphatics) and result in

    miliary TB.

Diagnosis of TB is done by Ziehl-Nilson stain (AFB stain) or by culture (note that a

    special AFB culture must be ordered, otherwise nothing will grow!)

Ok, I think we are done with infections of the lung. Remember, the second category of

    restrictive diseases are “Miscellaneous”(refer back to the outline above, beginning of “restrictive” section)

Miscellaneous Restrictive Diseases of the Lung

    A. Pneumoconioses = lung infection due to inhalation of a substance

    a) anthracosis, aka, coal workers’ penumonociosis. (CWP). Remember that

    anthrocotic pigment is the only black pigment known to mankind. These

    patients are usually asymptomatic and rarely develop fibrosis. Lung

    macrophages usually eat up the pigment.

    b) Silicosis: these lesions are fibrotic and nodular. In other words, this is a

    more serious business than anthrocosis.

    c) Asbestosis: patients’ lungs fibrose, but this fibrosis is not nodular. There

    is diffuse pulmonary interstitial fibrosis. Histology: we’ll see thickening

    of septa due to fibrosis and ferruginous bodies (asbestos fibers covered

    with glycoprotein and hemosiderrin

    B. Sarcoidosis, aka, granulomatous inflammation of unknown etiology.

    This is a systemic disease where lungs are involved 90% of the time. Eye and

    skin lesions are next in frequency. These granulomas, unlike those seen in TB,

    are non-caseating. Females are affected more often than males. Blacks are

    affected more often than whites.

    C. Diffuse Idiopathic Interstitial Fibrosis, aka, Hamman-Rich syndrome

    Histologically, this could look similar to interstitial pneumonia or asbestosis.

    Grossly, there is honeycomb appearance of the lung.

D. DIP (Desquamative Interstitial Pneumonitis)

    There is inflammation of septa. The main response is from macrophages,

    which may fall into alveoli. Earlier, people used to think that there were

    epithelial cells falling into alveoli, not macrophages, hence “desquamative”

E. Hypersensitivity Pneumonitis.

    Note: this is different from asthma b/c alveoli, not bronchi are involved.

    Histologically, we again see thickened septa and also eosinophils (no surprise

    since this is a hypersensitivity reaction after all)

F. Pulmonary Eosinophilia

    We see lots of eosinophils in lung, with or without eosinophilia in blood.

    Simple pulmonary eosinophilia is aka Loffler syndrome.

    It could also be caused by parasitic, fungal, or bacterial infections.

G. BOOP (Bronchiolitis Obliterans Organizing Pneumonia)

    There is fibrosis of bronchioles. This is a common response to infections, and

    patients with BOOP generally tend to do well. Bronchiolar injury and repair

    distinguish patient with BOOP from patients with “regular” pneumonia, which

    does not involve bronchioles.

H. Diffuse Pulmonary Hemorrage Syndrome

    a) Goodpasture syndrome. As we learned in renal path, in this disease there

    are Abs planted on glomerular BM against collagen type IV. The same

    thing happens in the lung. This results in hemoptysis and eventually


    b) Idiopathic Pulmonary hemosiderosis. In this case, there is no renal disease

    involved, and no Abs planted. However, clinically this presents similar to

    Goodpasture syndrome with hemoptysis and anemia.

I. Pulmonary involvement in collagen vascular disorders

    Often seen with systemic sclerosis, SLE, RA. These may eventually lead to

    pulmonary fibrosis.

J. Pulmonary Alveolar Proteinosis

    Etiology of this disease is unknown. Histologicaly this disease is similar to

    PCC (pneumocystis) infection. We see bubbly proteinacious material in

    alveolar spaces.

    V. Lung Tumors

    Lung carcinoma and bronchgenic carcinoma are equivalent terms. Don’t get

    confused! “Lung cancer”, however, is a more general category which includes

    carcinomas, sarcomas, carcinoids, etc.

    Lung carcinoma accounts for 90-95% of all malignant tumors of the lung. There are 4

    types of carcinomas. Note, the following prevalences are somewhat different than those

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