LUNG PATHOLOGY

NORMAL

Embryonic origin? 

§    Outgrowth from ventral wall of foregut

Define airway segments*

§    Bronchi

§    Bronchioles: no cartilage, no submucosal glands

§    Terminal bronchioles: <2mm

§    Acinus[1] (respiratory bronchiole+alveolar duct+alveoli): anything distal to terminal bronchioles, about 7mm in diameter

Define lobules*

§    Cluster of 3-5 terminal bronchioles

Composition of alveolar septum?

§    Endothelium

§    BM

§    Interstitium

§    Alveolar epithelium

§    Alveolar macrophages

What’s in pulmonary interstitium?*

§    Fused BM

§    Fine elastic fibers

§    Small bundles of collagen

§    FB

§    SM cells

§    Mast cells

§    Rare lymphocytes and macrophages

§    Megakaryocytes in BV (some PLT are generated in lungs!)

Functions of pneumocyte II?*

§    Surfactant (osmiophilic lamellar bodies)

§    Repair cells

Anatomy

§    Bronchi: mainstemà lobar (1^st order)à segmental

§    Bronchioles: no cartilage and submucosal glands

§    Regional lymph nodes: paratracheal, pre- and retrotracheal, aortic, subcarinal, periesophageal, inferior pulmonary ligament, hilar, peribronchial, intrapulmonary

§    Lymphatics: not present in alveolar walls

Cells

§    Type I pneumocytes: 95%, flattened

§    Type II pneumocytes: 5%, surfactant (lamellar bodies), involved in repair

§    Clara cells: increase towards terminal bronchiole

Ø   Secretory function

Ø   Progenitor cell after bronchiolar injury

§    NE cells: numerous in neonates but rare in adults

Pearls for biopsies

§    Tips of lingula and right middle lobe more fibrosis than elsewhere

§    Elastic and trichrome helpful in non-neoplastic tissue

 

CONGENITAL ANOMALIES

5 congenital diseases and describe*

§    Pulmonary hypoplasia[2]*: small lungs (weight, volume, acinar number)

§    Foregut cysts*: abnormal detachment of foregut, often in hilum or middle mediastinum. Usually incidental but may be infected or rupture

§    Cystic adenomatoid transformation*: hamartoma, 5 types (from 0-4)

Ø   Type 1 (no1): large cysts lined by respiratory epitheliumà good prognosis with resection

Ø   Type 2: medium-sized cystsà poor prognosis, other malformations

Ø   Other types: rare

§    Pulmonary sequestration: pulmonary lobe or segment without normal connection with airways and with blood supply from aorta (rather than pulmonary artery)

Ø   Extralobar (thorax, mediastinum): in infants as mediastinal mass in association with other congenital anomalies

Ø   Intralobar: in older kids and adults, often acquired and associated with recurrent infections

§    Other

Ø   Congenital lobar pneumonia

Ø   Tracheal anomalies: atresia, stenosis, TEF

Ø   Vascular anomalies

Ø   Congenital lobar overinflation (emphysema)

Causes of pulmonary hypoplasia*

§    Intra-uterine space occupying lesions (diaphragmatic hernia), oligohydramnios, impaired fetal breathing, anencephaly, renal cystic diseases

Classify foregut cysts

§    Bronchogenic[3]: lined by respiratory epithelium with focal squamous epithelium, contains submucosal glands, cartilage and SM. No communication with airways. Can become infected

§    Enteric

§    Esophageal

 

ATELECTASIS

3 main types and causes*

§    Resorption: due to airway obstruction (bronchial asthma) followed by resorption of trapped O2. Mediastinum shifted toward* affected side

§    Compression: pleural effusion, tension pneumothorax, ascites. Mediastinum shifted away* from affected side

§    Contraction[4]: scars in lung or pleura preventing full expansion

 

MIDDLE LOBE SYNDROME

§    What???

§    Bronchiectasis is an important component of middle lobe syndrome

 

PEDIATRIC

BRONCHOPULMONARY DYSPLASIA

Etiology

§    Prematurity

Outcome

§    Respiratory distress continues for monthsà limited pulmonary reserveà repeated infections, pulmonary HTNà cor pulmonale

Micro

§    Bronchiolar and interstitial fibrosis, compensatory emphysema of less damaged acini, inadequate alveolar development causes fewer but larger alveoli

ACUTE LUNG INJURIES

Name 3 acute injuries

§    Pulmonary edema

§    ARDS

§    Acute interstitial pneumonia

 

PULMONARY EDEMA

Classify causes and give examples*

§    Hemodynamic

Ø   Increased hydrostatic pressure: left heart failure

§    Microvascular injury

Ø   Smoke inhalation

§    Idiopathicà high altitude

Micro for cardiogenic pulmonary edema

§    Edema

§    Chronic: interstitial fibrosis + intra-alveolar heart failure cells[5][6]à impaired respiration and increased infections

2 complications of pulmonary edema

§    Respiratory failure

§    Prone to infections

 

DIFFUSE ALVEOLAR DAMAGE

Mechanism of ARDS

§    Microvascular injury (endothelium) that eventually spreads to alveolar epithelium

Treatment response?

§    No response to O2, leading to respiratory acidosis

Etiologies (6)***

§    Infections

Ø   Sepsis (common)

Ø   Pulmonary infection (viral, Mycoplasma) (common)

§    Liquid

Ø   Near-drowning

Ø   Gastric aspiration (common)

§    Gas

Ø   Smoke

Ø   O2

Ø   NO2: silo-filler

§    Trauma

Ø   Head (common)

Ø   Lung

§    Shock

Ø   Acute pancreatitis

§    Treatment

Ø   Bleomycin (chemotherapy)

Ø   Heroin

Ø   Radiation

§    Transfusion

§    Idiopathic[7]

PFT?

§    Restrictive (prototype)

3 stages with macro and micro*. When is peak?

Exudative (first week)	Heavy, firm[8]	-Interstitial edema[9]  -Hyaline membrane[10] -Acute septal inflammation[11]
Proliferative/organizing[12]		-Pneumonocytes II HP  -Interstitial FB and MFB -Intimal thickening
Fibrotic		-Interstitial fibrosis[13]  -Cystic changes

Difference between infantile and adult*

§    Lack of surfactant in kids vs diffuse capillary injury in adults

Why is ARDS nasty compared to pulmonary edema?

§    Exudate and lung damage difficult to heal, often lead to organization and scarring

§    Pulmonary edema often resolves without scarring

Is it a diffuse process?

§    Functional abnormality is patchy, creating ventilation-perfusion mismatch (non-ventilated areas being continuously perfused)

Mechanism: which cell type plays central role?*

§    Gram-organisms release endotoxinà activates complement, monocytes and macrophages to release mediators (IL-1, IL-8, TNF)

Ø Toll-like receptorsà upregulation of NF-κBà activation of immune response

§    TNF activates PMN*à release mediators which cause local damageà macrophages sustain ongoing inflammation

Prognosis

§    Severeà 50% mortality

§    Survivors may evolve toward honeycomb lung!

Treatment

§    Ventilator with increased O2 requirement

 

ACUTE INTERSTITIAL PNEUMONIA

Define

§    Exactly same as ARDS except unknown etiology

Prognosis

§    As bad as ARDS[14]

 

OBSTRUCTIVE LUNG DISEASES

Causes of obstructive lung disease

§    Emphysema

§    Chronic bronchitis

§    Bronchiectasis

§    Asthma

§    Bronchiolitis

Site of disease

§    Bronchi: chronic bronchitis, bronchiectasis, asthma

§    Bronchioles: bronchiolitis

§    Acini and respiratory bronchioles: emphysema

Based on what is obstructive vs restrictive?

§    PFT

Lab test differences and causes

§    Obstructive: reduced maximal airflow rate during force expiration (FEV1)

Ø   Obstruction

Ø   Loss of elastic recoil

§    Restrictive: reduced total lung capacity, normal FEV1

Ø   Chest wall problems

Ø   Acute or chronic interstitial or infiltrative diseases

 

 

EMPHYSEMA

Define

§    Abnormal permanent enlargement of airspaces distal to terminal bronchioles with alveolar wall destruction and minimal fibrosis

SSx

§    Asymptomatic until 1/3 of functional capacity is lost

Gross

§    Bullae-alveolar space >1cm

4 types* of emphysema and acinar locations*?

Centriacinar/centrilobular  -Proximal acini (respiratory bronchioles)[15]* -Peribronchial and peribronchiolar inflammation -Worse in upper lungs (less circulating A1AT here)	-Smoking  -Chronic bronchitis -CWP[16]
Panacinar/panlobular  -Distal acini (alveolar sacs and ducts)à proximal acini (respiratory bronchioles)* -Worse in lower lobes (because more PMN here), voluminous lungs	-A1AT[17]*  -Talc IVDU -Ritalin use
Paraseptal/distal acinar  -Distal acini* -Worse in upper[18] lungs, adjacent to pleura	-Spontaneous pneumothorax
Irregular[19]  -Acinus irregularly involved*	Scar

Other emphysemas (hint: I C SOB)

Interstitial	-Air entry into stroma of lung, mediastinum, subcutis
Compensatory	-Overinflation of alveoli without tissue destruction
Senile[20]
Obstructive overinflation	-Air trapping[21]
Bullous (≥1cm)

 

 

Genetics:

§    Normal: PiMM

§    Hetero: PiMZ

§    Homo: PiZZ

Protease-antiprotease theory (2). Explain how smoking contributes to emphysema (3)

§    Smoking

Ø   Activates alveolar macrophagesà attracts PMNà neutrophilic[22] elastase

Ø   Enhances macrophage and neutrophil elastase activity

Ø   Produces abundant free radicalsà depletes natural anti-oxidant mechanism

§    Decrease antiprotease (PiZZ) and increased elastaseà protease-antiprotease imbalanceà emphysema

Gross

§    Panacinar: huge lung

§    Centriacinar: more subtle but worse in apex (blebs, bullae)

Micro

§    Enlarged alveolar spaces from wall destruction

§    Thin alveolar septa (minimal fibrosis)

§    Compression of septal capillariesà bloodless

§    >1cm alveolar space (blebs and bullae) if rupture

Clinical

§    Pink puffer: dyspnea, hyperventilation, weight loss, pursed lips, barrel chest, variable cough and sputum

Bad prognosticators

§    Pulmonary HTN

§    Cor pulmonale

3 major causes of death

§    Respiratory acidosisà coma

§    Core pulmonale

§    Pneumothorax

 

CHRONIC BRONCHITIS

Define

§    Productive cough for at least 3 months in at least 2 consecutive years

2 factors important in the pathogenesis

§    Cigarette smoking

§    Infections

Clinical

§    Blue bloater: hypercapnia, hypoxia, recurrent infections, severe hypoxemia, cough and sputum, cyanosis

Variants (3)

1.  Simple chronic bronchitis: productive coughs but no obstruction

2.  Asthmatic chronic bronchitis: hyperreactive airways (wheezing)

3.  Obstructive chronic bronchitis: associated emphysema

Gross: autopsy findings?

§    Erythematous and edematous mucosa

§    Mucopurulent secretion (casts when severe) in bronchi and bronchioles

§    Cor pulmonale, ascites, pedal edema

§    Pulmonary HTN

§    +/-pneumonia

Mechanism by which smoking cause chronic bronchitis (4)

1.  Mucus hypersecretion with submucosal gland hypertrophy in trachea and bronchi (earliest event)[23]

2.  Goblet cell metaplasia in bronchioles[24]

3.  Bronchiolitis

4.  Secondary infections[25]

How does smoking promote infections?

1.  Direct epithelial injury

2.  Interferes ciliary action

3.  Inhibits bronchial and alveolar leukocytes

Micro: 2 characteristic findings? What happens when severe*?

§    Mucin plugs/casts in bronchioles

§    Increase goblet cells in small airways

§    Squamous metaplasia and dysplasia

§    Increased mucous gland size[26] in large airways

§    Chronic inflammation and fibrosis[27] in entire airways

What is the Reid Index? What’s abnormal?

§    Mucous gland thickness/bronchial wall thickness[28]

§    N=0.4. Increased value proportional to severity and duration of chronic bronchitis

Complications

§    Cor pulmonale (RVH!)

§    Lung cancer

Chronic bronchitis	Emphysema
Bronchi	Acini
Clinical definition  -Cough with sputum for ≥3 months in last 2 years	Anatomic definition  -Permanent dilation distal to terminal bronchioles with wall destruction[29]

 

 

ASTHMA

Define*

§    Chronic relapsing inflammatory disorder characterized by paroxysmal reversible bronchospasm of tracheobronchial airways due to SM hyperreactivity

SSx*

§    Wheezing

§    SOB

§    Chest tightness

§    Cough

§    Worse at night or early morning

Incidence of asthma for past 3 decades?*

§    Increasing!

Different classification schemes

§    Severity

§    Response to therapy

§    Triggering agents

§    Pathophysiology

What are 4 types of asthma and give an example?*

§    Atopic/extrinsic (type I HS)[30]: dust, pollen, food, family history of atopia

§    Non-atopic/intrinsic (non-immune)[31]: common cold, aspirin, stress, irritans, exercise

§    Drug-induced: ASA[32]*

§    Occupational: resin, fumes

§    Others

Ø   Seasonal

Ø   Asthmatic bronchitis

Mechanism of atopic asthma*

1.  Sensitization to allergen

Ø   Th2* response to allergenà IgE production by Bà IgE binds to mast cellsà eosinophil recruitment

2.  Re-exposure

Ø   Initial phase: Ag binds to IgE AB on mast cells and basophilà degranulation of preformed mediators (cytokine, neuropeptide) and de novo synthesis (leukotriene)à recruitment of PMN, mast cells and eosinophils, vasodilation, increased vascular permeability, glandular secretions and epithelial damage

Ø   Late phase (starts 4-8h after onset, lasts up to 24h): mediated by recruited inflammatory cells from initial phaseà characterized by persistent bronchospasm[33], edema, inflammation and epithelial damage[34]

Gross (2)*

§    Overinflation with focal atelectasis (caused by mucus plugs[35])

Micro: concept of airway remodeling.

§    Allergic mucin containing eosinophils, Curschmann spirals and Charcot-Leyden crystals (eosinophils’ membrane protein)

§    Goblet cell metaplasia

§    Thick BM

§    Inflammation infiltrating walls (mast cell, eosinophils, macrophages, PMN, lymphocytes)

§    Mucous gland HP

§    SM HP[36]

What’s status asthmaticus*? How to diagnose?

§    Severe acute onset with persistence up to weeks due to exposure of previously sensitized antigen, leading to hypoventilation, cyanosis and death[37]

§    Peripheral eosinophilia and Curschmann spirals, Charcot-Leyden crystals in sputum

 

BRONCHIECTASIS

Definition*

§    Abnormal permanent dilation of bronchi and bronchioles from necrotizing infection[38]

SSx

§    Characteristic sudden cough triggered by position especially in morning (due to pooling of pus in bronchi)

Causes of bronchiectasis (3) and examples of each*. Name a few bugs

§    Obstruction: tumour, FB

§    Congenital: Kartagener’s[39], CF, intralobar lung sequestration, immunodeficiency, primary ciliary dyskinesia

§    Postinfectious[40]: necrotizing bacteria, viruses or fungal

§    Others: rheumatoid arthritis, SLE, IBD, post-transplantation (rejection or GVHD)

2 requirements for pathogenesis*

§    Obstruction

§    Infections

Gross features (2)[41].

§    Cylindroid, fusiform, saccular[42][43]

§    Dilated[44] bronchioles[45] which follow out to pleura (N=spared peripheral 2-3cm)

§    Thick mucopurulent secretions

§    Worst areas in distal bronchi and bronchioles of lower lobes bilaterally[46]

Complications (3)

§    Respiratory failure

§    Fatal hemoptysis

§    Cor pulmonale

§    Metastatic abscesses

§    Amyloidosis

Micro features (4)

§    Spectrum of mild chronic to acute necrotizing inflammation[47] of larger airways with peribronchial fibrosis leading to total luminal obstruction

§    Sometimes NE cell hyperplasia (tumorlets)

What germs?

§    Mixed except ABPA

Diagnosis

§    HRCT highly sensitive/specific and is current diagnostic gold standard. Diagnosis based on 1 of following criteria:

Ø   Internal bronchial diameter greater than adjacent bronchial artery

Ø   Lack of bronchial tapering

Ø   Bronchi visible within 1cm of costal pleura or bronchi visible abutting mediastinal pleura (AFIP)

§

RESTRICTIVE LUNG DISEASES[48]

Give 3 patterns of interstitial diseases

§    Diffuse without architectural distortion (dusty web)

§    Patchy: subpleural vs bronchocentric

§    Random

Incidence by etiologies

§    Environmental (25%)

§    Sarcoidosis (20%)

§    UIP (15%)

§    Collagen vascular diseases (10%)

§    The remaining 10% is from hundred of etiologies

Patterns of injury

§    Interstitial inflammation/fibrosis: DIP, UIP, DAD, histiocytosis

§     X, amyloidosis, HSP, pneumoconiosis, radiation

§    Intraalveolar:

§    Small-airway: BO, RB-ILD, HSP, eosinophilic pneumonia

§    Large-airway: ABPA, TB, fungi, Wegener’s

§    Granulomatous vasculitis: Wegener’s, sarcoidosis, Churg-Strauss

§    Small vessel: pulmonary HTN, thromboembolism, polyarteritis nodosa, veno-occlusive disease, Churg-Strauss

§    Hemorrhage: Goodpasture’s, SLE, idiopathic pulmonary hemosiderosis, Wegener’s

§    Lymphoid: LIP, lymphoma, lymphoid aggregates, HSP

§    Eosinophils[49]: eosinophilic pneumonia, allergic to drugs, Churg-Strauss, Langerhans cell histiocytosis, asthma

 

1. FIBROSING DISEASE

Types

§    UIP

§    NSIP

§    COP

§    Collagen vascular diseases

§    Pneumoconiosis

§    Drug reactions

§    Radiation pneumonitis

Common clinical, radiologic and pathologic features*

§    Clinical: dyspnea, decreased lung volume, decreased compliance

§    Radiologic: diffuse ground glass infiltrate

§    Pathologic: diffuse chronic inflammation, fibrosis of interstitium

Mechanism

§    Initiation: epithelial or endothelial injury by inhaled or blood-borne toxins or agents

§    Early: alveolitisà recruitment of inflammatory cellsà FB proliferation under fibrogenic factors

§    Late: fibrosis

 

USUAL INTERSTITIAL PNEUMONIA (UIP)

Etiology***

§    Idiopathic, previous URTI

Mechanism

§    Repeated cycles of alveolitis (reason why temporally heterogeneous) cause abnormal wound healing resulting in excessive FB proliferation

Associations

§    RA, scleroderma

Who and how?

§    40-70, slow progressive SOB, cough, clubbing, hypoxemia

§    Leads to cor pulmonale and RHF if severe

Gross

§    Worse in lower lungs

§    Pleural cobblestoning

§    Honeycomb

Micro*

§    Patchy interstitial fibrosis[50], worse in subpleural area, interlobar and lower lobes

§    New fibroblastic foci[51]

§    Honeycomb lined by hyperplastic type II pneumocyte

§    Focal squamous metaplasia

§    Temporally heterogeneous

§    Must correlate with clinical, radiographic and laboratory findingsà diagnosis of exclusion

§    Mild-moderate mixed interstitial inflammation

§    Pulmonary HTN change often (intimal fibrosis, medial SM HP)

IHC

§    Movat: foci green, fibrosis yellow

§    Masson trichrome: fibrosis blue

How to predict progression? Definitive treatment

§    Impossible because some have sudden rapid decline (death within 3 years)

§    Transplantation

 

NONSPECIFIC INTERSTITIAL PNEUMONIA (NSIP)

Define

§    Groups of diffuse interstitial lung disease with unknown etiologyà wastebasket diagnosis

Why important?

§    Much better prognosis than UIP

Clinical

§    SOB, cough, fever for several months

Micro*

§    Cellular[52] or fibrotic[53] or mixed

§    Diffuse

§    Temporally homogeneous

§    No fibroblastic foci

Why separate cellular vs fibrotic?

§    Cellular younger and better prognosis

CRYPTOGENIC[54] ORGANIZING PNEUMONIA

Why COP is preferred?

§    BOOP

§    Confers information that it’s cryptogenic and avoid confusion with BO (bronchiolitis obliterans)

Clinical***

§    Cough and dyspnea

§    Recent RTI, inhaled chemicals, recent drugs, collagen vascular disease, lung transplant

Mechanism

§    Idiopathic or response to infection or inflammation

Etiology (hint: I DIC)***

§    Infections (viral, bacterial)

§    Inflammation

Ø   Inhalents (silo-filler lung)

Ø   Collagen vascular disease

Ø   GVHD

§    Drugs

Micro

§    Loose fibrous tissue plugs (Masson bodies) in alveoli, alveolar ducts and bronchioles

§    Temporally homogeneous

§    Normal lung architecture, alveolar walls fairly normal

§    No: interstitial fibrosis, interstitial inflammation, honeycomb, granulomas[55]

Prognosis

§    Excellent with CTSD

 

BRONCHIOLITIS OBLITERANS

Aka

§    Constrictive bronchiolitis

Prognosis vs BOOP?

§    Much worse than BOOP

Define

§    Fibrosing disease leading to constrictive scarring of small airways

Etiology

§    Chronic rejection in transplant

§    Collagen vascular disease

§    Adenovirus infections in kids

§    Fume/dust injuries

§    Distal to bronchiectasis

§    Idiopathic

Incidence

§    Quite rare

§    Prognosis: much poorer than BOOP (Osler).

Micro

§    Early: peribronchiolar fibrosis

§    Old: scar at location of pre-existing bronchioles[56]

§    When start organizing, can form peribronchiolar fibrosis (Steinberg).

 

COLLAGEN VASCULAR DISEASES

Some collagen vascular diseases affecting lungs (hint: DR. ASS)

§    Dermatomyositis/polymyositis

§    Rheumatoid Arthritis

§    Scleroderma

§    SLE

§    Mixed connective tissue disease

Different patterns of injury?

§    NSIP: scleroderma* (classic)

§    UIP

§    Vascular sclerosis

§    COP

§    Bronchiolitis (small airway disease with or without fibrosis)

4 forms of pulmonary rheumatoid arthritis[57]

§    Chronic pleuritis without or without effusion

§    Diffuse interstitial pneumonitis or fibrosis

§    Intrapulmonary rheumatoid nodules

§    Pulmonary HTN

Why important to recognize pulmonary involvement

§    Worse prognosis but still better than UIP

 

2. PNEUMOCONIOSES

What is Caplan syndrome?

§    Nodular pulmonary nodules from combination of RA and pneumoconiosis

What does it include?

§    Organic

§    Inorganic

§    Chemical fumes

2 more common causes of progressive massive fibrosis? (PMF)

§    CWP

§    Silicosis

What determines harmfulness of particle?*

§    Amount of dust retained in lung: concentration, duration, effectiveness of clearance mechanisms

§    Size, shape and buoyancy

Ø   >5µm: filtered in upper airways

Ø   1-5µm: go in alveoli and get trapped

Ø   ≤1µm: in and out freely

§    Particle solubility and reactivity[58]

§    Other irritants (smoking)

Most dangerous size?*

§    1-5µm because can reach air sacs

 

COAL WORKERS PNEUMOCONIOSIS

3 types of CWP and etiology

1.  Anthracosis: small harmless accumulations in smokers and urban dwellers

2.  Simple CWP: more prominent aggregates of coal dust-laden macrophages forming coal macules

Ø   Clinically, cough with black sputum but no significant dysfunction

3.  Complicated CWP or progressive massive fibrosis[59][60]: severe fibrosis and scarring, significant dysfunction

Micro

Anthracosis	-Pigments in macrophages  -Interstitium along lymphatics -Organizing lymphoid follicles
Simple CWP	-Black coal macules (1-5mm) consisting of carbon-laden macrophages  -Lobar upper[61] zones -Develop centriacinar emphysema*
Complicated CWP (<10%)	-Black scars (2-10cm) and central ischemic necrosis  -Mostly in upper zones -Pulmonary HTNà cor pulmonale

Other complications?

§    No evidence of cancer

What determines progression or not?*

§    Duration

§    Intensity of exposure

§    Secretion of fibrogenic factors by coal dust-laden macrophages

 

SILICOSIS

Consequence

§    Causes nodular dense pulmonary fibrosis

Special about incidence

§    No1 chronic occupational disease in world

Name what workers?

§    Sandblasters, miners, ceramics, metal workers, quartz workers

Mechanism

§    Ingestion by macrophagesà activation of macrophagesà release of fibrogenic factors (especially TNF)*à fibrosis

§    Direct toxicity[62][63] to macrophagesà lysis of macrophagesà repeated cycle

Micro

§    Acute: pulmonary alveolar proteinosis

§    Chronic:

 

Imaging and PFT

§    Fine nodularity mostly in upper lungs (just like CWP)

§    Normal or only mildly affected (no SOB until PMF kicks in)

Sequence of events? What’s in LN?*

1.  Tiny collagenous nodules[64] starting in upper lung

2.  Larger and coalesce to form large areas of scar

Ø   Concentric hyalinized whorls[65] of collagen, birefringent crystals, scant inflammation

Ø   Some in hilar LN (eggshell calcification*) or pleura

3.  PMF[66]

Prone for which infection?

§    TB

Carcinogenic?

§    Controversial

 

ASBESTOSIS

5 diseases linked to asbestos

§    Asbestosis

§    Mesothelioma

§    Bronchogenic carcinoma

§    Laryngeal carcinoma

§    Pleural plaques (rarely diffuse pleural fibrosis)

§    Pleural effusions (serous)

§    Diffuse interstitial fibrosis (asbestosis)

What dictate pathogenesis?

§    Size

§    Shape

§    Concentration

§    Solubility

2 types*

§    Serpentine[67] (no1, white): chrysotile

Ø   Curvy, flexible, more soluble

§    Amphibole[68] (blue for bad): crocidolite, amosite, tremolite, anthophyllite, actinolyte

Ø   Straight, stiff, brittle

Gross: difference with silicosis?* Importance?

§    Asbestosis is diffuse interstitial fibrosis whereas silicosis is nodular interstitial fibrosis.

§    Asbestosis lower lungs vs upper lungs in silicosis

§    Therefore asbestosis indistinguishable from most other interstitial lung fibrosis except presence of asbestosis bodies

Micro

§    UIP-like: exactly same both macro-[69] and microscopically except asbestos bodies[70]

§    Minimal inflammation

§    Pleural plaques[71][72][73]: basket-weave dense collagen, often calcified

Describe asbestosis bodies*.

§    Golden brown fusiform or beaded rods

§    Center: translucent asbestos fibers

§    Periphery: iron-containing proteinaceous material

Mechanism

§    Asbestos ingested by macrophages[74]à release of complement C5a and chemoattractantsà

Ø   Enzymes or free radicals by macrophages and recruited PMN

Ø   Fibrogenic factors released by macrophagesà fibrosis

Ø   Direct stimulation of FB collagen synthesis by asbestos

Where to find asbestosis bodies?

§    Mesothelioma: nearly never

§    Pleural plaques: never

§    LN: best

§    Effusion: ?

§    Sputum: yes

§    Parenchyma: best (around airways)

Can asbestosis bodies be found in normal?

§    Yes, minimal amount

What are ferruginous bodies?*

§    Same but center is not asbestos but different minerals

What’s considered significant exposure?

§    >1/2cm² (Osler but Reza says 2/cm² in his lecture)

3 methods to detect asbestos bodies***

§    Careful histologic examination on H&E

§    Iron stain

§    Javex digestion (then submit to cytology)à submit 5g from lower lobes and Prussian

§    EM[75]

How to confirm asbestos?

§    By special biophysical method (electron microprobe analysis), not by EM (Steinberg)

SSx

§    SOB, cor pulmonaleà CHF

Can it cause peritoneal mesothelioma? What about tunica vaginalis?

§    Peritoneal: yes!

§    Tunica vaginalis:

BERYLLIOSIS

Which occupations?

§    Airspace metal, computer, metal salvaging

§    Genetic susceptibilityà delayed type HSà non-caseating granulomas along lymphatics[76]à multiple become fibrotic

GIANT CELL INTERSTITIAL PNEUMONIA

Etiology

§    Hard metals like tungsten, carbide, cobalt

Micro

§    Intra-alveolar (not interstitial) cannibalistic MGC

SYNTHETIC FIBER

§    Aka nylon flock worker’s lung

Micro

§    Peribronchovascular lymphocytic infiltrates with lymphoid follicles (Lit)

DRUGS

Name some drugs toxic to lungs

§    Bleomycin: fibrosis

§    Amiodarone: pneumonitis

Patterns

§    Acute

Ø   Bronchospasm

Ø   Pulmonary edema

§    Pneumonitis

Ø   Eosinophilic pneumonia

§    Fibrosis

Ø   Interstitial fibrosis

Ø   Bronchiolitis obliterans

METHOTREXATE

2 organs of injury

§    Liver: macrovesicular steatosis

§    Lung: DAD, granulomas, UIP Us

Onset?

§    Within 6 months

RADIATION PNEUMONITIS

Micro: what’s the acute pattern and what happens later

§    Acute pneumonitis (DAD type) 1-6 months after therapy, followed by fibrosis

3. GRANULOMATOUS DISEASES

SARCOIDOSIS

Define

§    Systemic[77] granulomatous disease of unknown etiology

SSx

§    Asymptomatic

§    Aggressive onset: fever, erythema nodosum, polyarthritis

§    Insidious: SOB, constitutional (fever, weight loss, fatigue)

Organs affected in order of frequency

1.  Lungs[78]: granulomas tend to heal

2.  Lymphadenopathy (≈100%): tonsils (1/4)

3.  Eye and lacrimal glands (up to 1/2): iritis, iridocyclitis or choroid retinitisà visual impairment

4.  Salivary glands: bilateral sarcoidosis of all salivary glands and eye involvement called Mikulicz syndrome

5.  Skin (up to 1/2): subcutaneous nodule (erythema nodosum), also on mucosa

6.  Spleen (3/4 with microscopic evidence): but only 1/5 have splenomegaly

7.  Liver: more in portal triads. Hepatomegaly rare

8.  Marrow (1/5)

9.  Muscle: muscle biopsy may be useful for diagnosis. Often asymptomatic

Micro: describe Schaumann and asteroid

§    Non-caseating granulomas + GC

§    Schaumann[79] and asteroid[80] bodies

§    Become fibrotic with fibrous rims with time

Mechanism (3)*

§    Immunologic

§    Genetics

§    Environment: Propionibacterium acnes, Rickettsia

Diagnosis

§    Suggested by clinical history: high serum IgG, hyperCa, characteristic imaging

§    Biopsy documenting noncaseating granulomas[81] required for diagnosis (liver, lung, LN).

What’s abnormal in lymphocytes in BAL?

§    CD4/CD8 >2.5

§    CD3/CD4 <0.31

Lethal complications?

§    Pulmonary fibrosis

§    Neurosarcoidosis

§    Cardiac conduction system

Staging*

1.  Hilar LN

2.  Hilar LN+pulmonary infiltrate

3.  Pulmonary infiltrate

4.  Honeycomb?

Evolution of sarcoidosis[82]

§    Slowly progressive with 10% died from pulmonary fibrosis

§    Up and down (relapse and remission)

§    Spontaneous resolution

HYPERSENSITIVITY PNEUMONITIS (EXTRINSIC ALLERGIC ALVEOLITIS)

Etiology

§    Organic dusts, occupational antigens

Types (hint: The Bird Mus B Pi)***

§    Thermophilus Bird Mushroom Bark Pigeon

Ø   Farmer’s: spores of thermophilic actinomycetes in hay

Ø   Pigeon fancier’s: proteins from bird feathers or excreta

Ø   Air-conditioner lung: thermophilic bacteria (Actinomyces)

Ø   Mushroom

Ø   Bark

Difference from asthma, which is also allergic?*

§    HSP involves mainly alveoli whereas asthma mainly bronchi

What HS reactions?*

§    III and IV (granulomas)

Clinical***

§    Acute (4-6h after exposure): fever, cough, SOB, leukocytosis, diffuse or nodular lung infiltrates on CXR, restrictive PFT

§    Subacute:

§    Chronic: cyanosis, worsening SOB

Imaging

§    Peripheral infiltrate (mirror image of pulmonary edema)

Micro***

§    Bronchiolitis obliterans (late): intrabronchiolar fibroblastic plug with foam cells and cholesterol clefts

§    Bronchocentric intersitial pneumonitis[83] and fibrosis

§    Loose, noncaseating granuloma: 2/3

§    Other

Ø   Temporally homogeneous

Ø   Intra-alveolar infiltrate in >50%

Ø   No: eosinophils, PMN

 

 

4. PULMONARY EOSINOPHILIA

Name 5 types*

§    Idiopathic

Ø   Simple pulmonary hypereosinophilia (Löffler syndrome)

§    Transient lesion, often asymptomatic, serum eosinophilia, benign

§    Alveolar septa thickened by eosinophils and giants, no vasculitis, no fibrosis, no necrosis

Ø   Acute[84] eosinophilic pneumonia with respiratory failure

§    Rapid onset, fever, SOB, hypoxemic respiratory failure

§    >25% eosinophils in BAL

§    DAD under microscope

Ø   Chronic eosinophilic pneumonia

§    Focal lung consolidation

§    Secondary: parasites (microfilaria), fungi (ABPA no1), bacteria, HSP, drugs, asthma, vasculitis (Churg-Strauss), hypereosinophilic syndrome

Which HS?

§    All via HS1 (IgE-mediated)

Evolution

§    Acute, tropical and simple self-limited

 

 

CHRONIC EOSINOPHILIC PNEUMONIA

SSx

§    Prolonged cough, fever, blood eosinophilia

Micro (hint: 3 compartments)

§    Alveoli: eosinophils, lymphocytes, plasma cells, macrophages, edema

§    Interstitium: eosinophils, lymphocytes, plasma cells

§    Bronchiolitis obliterans

§    Diagnosis of exclusion

Treatment

§    CTSD

ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS[85]

Characteristics

§    Intense eosinophilic infiltrate in airways with thick much plugs which plays important role in pathogenesis

§    Episodic leading to proximal bronchiectasis and fibrotic lung disease

§    Allergic reaction, not infectious but bug is present

SSx

§    Prolonged cough, fever, blood eosinophilia, very high serum IgE, serum antibody against Aspergillus fumigatus*

Clinical: who has this?*

§    CF

§    Asthma

Micro*

§    Allergic mucous bronchiole plugs + bronchiectasis

§    Bronchocentric necrotizing granuloma (Steinberg)

§    Fungus in mucus[86] but may invade in late stage

§    Dichotomous (into two nearly equal branches) branching, septate hyphae, often invade BV

§    Vasculitis???

5. SMOKING-RELATED INTERSTITIAL DISEASES

HISTOCYTOSIS X

Clinical: RF

§    Mid-aged (30-40) males, exclusively in smokers

§    Asymptomatic despite abnormal CXR

§    CP only if spontaneous pneumothorax

Lab: eosinophilia?

§    No peripheral eosinophilia

Micro

§    Stellate fibrous scar

§    Nodules of Langerhans cells[87][88] in interstitium around bronchioles[89] and BV and in septa

§    Often: hemosiderin, eosinophils[90], reactive mesothelials, pigmented alveolar macrophages, cavitary necrosis

§    Permitted: mitoses up to 5/10, necrosis (often surrounded by “eosinophilic microabscesses”), moderate atypia of Langerhans (AFIP)

§    With time: lymphocytes replace eosinophils, more fibrosis leading to an acellular stellate scar (burn-out EG)

EM

§    Birbeck granules (pentilamellar intracytoplasmic structure, tennis racket); not always tennis racket morphology

Nature of Langerhans’ cells

§    Accessory immune system[91] in skin, LN, thymus

Complications

§    Spontaneous pneumothorax

§    PCP

Imaging

§    Diffuse bilateral interstitial or reticulonodular infiltrate in upper[92] lung, thin-walled cysts in CT

§    Single or multiple nodules in rare cases

§    Honeycomb when late stage

Locations

§    20% with multicentric disease (bone, skin, LN, spleen, pituitary) have lung involvement

§    50% only involve lung

Outcome

§    Favorable with resolution or stabilization (with treatment)

§    But 10-20% progress into respiratory failure

IHC

§    CD1a+: membrane, more specific but less sensitive than S100, best on frozen tissue

§    S100+: nuclear and cytoplasmic

§    Langerin+

§    VIM+

DESQUAMATIVE INTERSITIAL PNEUMONITIS

Relationship with RB-ILD? Why misnomer?

§    Same spectrum

§    Not true desquamated pneumocytes but rather macrophages

Who and how?

§    40-50 males always[93] smokers, insidious onset of dry cough and SOB over weeks-months, often clubbing

Micro

§    Intra-alveolar smokers macrophages[94]

§    Mild interstitial pneumonitis (lymphocytes and plasma cells and some eosinophils)

§    Minimal interstitial fibrosis

§    Coexisting centrilobular emphysema

How does it evolve?

§    Non-progressive in majority

§    Responds to CTSD or smoking cessation

RESPIRATORY BRONCHIOLITIS-INTERSTITIAL LUNG DISEASE (RB-ILD)

Who and how?

§    Same as DIP because same spectrum

When to use ILD?

§    Significant pulmonary symptoms

§    Abnormal PFT

§    Abnormal imaging

Micro

§    Same as DIP except around respiratory bronchioles

§    Diagnosis requires smoking within past 6 months (AFIP)

Evolution

§    Some will progress into fibrosis if untreated

6. PULMONARY ALVEOLAR PROTEINOSIS PAP

3 classes?*

§    Acquired (90%)

Ø   Idiopathic although auto-antibody against GM-CSF may play a role

Ø   Leads to impaired clearance of surfactant by macrophages

§    Congential

Ø   In newborns, rapidly fatal

§    Secondary

Ø   Exposure to irritating dusts or chemicals or

Ø   Immunosuppressed patients

How to diagnose (3)

Ø   Clinical: adults, insidious onset of productive cough with gelatinous material

§    Radiologic: diffuse bilateral opacification

§    Histologic: PAS+ fluid with cholesterol clefts

How IHC can differentiate congenital from other forms?

§    Congenital: only A and C surfactants

§    Other forms: all 3

What other test can you do?

§    EM: lamellar bodies

Complications

§    Secondary infections

§    Respiratory failure

Evolution?

§    Some benign course but some require BAL (only treatment)

§    Fatal for congenital unless lung transplant

EXOGENOUS LIPOID PNEUMONIA

Etiology

§    Exogenous fat accumulation in lung: most often mineral oil ingestion (constipation) or aspiration

Complications: is this serious?

§    Yes, can cause fibrosis (AFIP).

Treatment

§    BAL (Lit)

Micro

§    FB reaction and proliferative fibrosis

§    Large lipid vacuoles within intra-alveolar and interstitial macrophages

Variants

§    Endogenous: lung-produced lipoid material caused by poor clearance. Also called golden cholesterol pneumonia because of its yellow color grossly

Ø   Also in amiodarone toxicity or rarely in lipid storage diseases

VASCULAR

PULMONARY EMBOLISM

Origin?

§    Almost always embolic although rarely thrombotic[95]

Effects by embolus size*

§    Saddle emboli: acute cor pulmonale[96][97]à death

§    Medium emboli (20-35%): usually hemorrhage or infarction

§    Smaller emboli (60-80%)

Ø   Asymptomatic in healthy with functional bronchial artery[98]

Ø   Peripheral infarct[99] in heart failure patients

§    Recurrent small emboli: chronic cor pulmonale (due to right heart strain)à pulmonary HTN

Primary vs secondary hypercoagulable states*

§    Primary: factor V Leiden, prothrombin 20210A, hyperhomocysteinemia, antiphospholipid syndrome

§    Secondary: obesity, surgery, cancer, OCP, pregnancy, catheters, trauma, cancer, burns

2 effects

§    Respiratory

§    Hemodynamicà pulmonary HTNà acute RHF

Gross: describe it*. Locations of most infarcts?

§    Wedge shape, slightly raised, hemorrhagic infarct[100][101], fibrinous exudate on pleura (pleural friction rub)

§    Lower lobes in 3/4

Micro

§    Ischemic necrosis of alveolar walls, bronchioles and BV in background of hemorrhage

§    PMN if septic embolus[102]

What on ECG in patient with saddle PE?***

§    Electromechanical dissociation[103]

Non-thrombotic emboli

§    Air

§    Marrow (trauma, sickle cell)

§    Fat (trauma, surgery)

§    Amniotic fluid

§    FB (IVDU)

 

PULMONARY HYPERTENSION

Define

§    Mean pulmonary pressure reaches 1/4 of systemic pressure

Presentation

§    SOB, CP, syncope, sudden death

Imaging

§    Prominent PA trunk, RVH

Etiologies

§    Primary: primary plexogenic HTN (young women), low penetrance

Ø   Primary plexogenic

Ø   Pulmonary veno-occlusive disease[104]

§    Secondary

Ø   Lung

§    COPD

§    ILD

§    Obstructive sleep apnea

Ø   Left heart failure

§    Intracardiac L-to-R shunts

§    LA myxoma

§    Valvulopathies

Ø   BV

§    Recurrent PE (can be chronic shedding of tumor emboli too!)

§    Vasculitis

§    Others: phen-fen (anti-obesity drugs), bush tea, adulterated olive oil

Primary (50%) & sporadic (20%) pulmonary HTN

§    Inactivating mutations of BMPR2[105]à lack of vascular SM cell apoptosisà pulmonary HTN

Mechanism for secondary

§    Endothelial dysfunction and injury (chemical or diet)à persistent vasoconstrictionà intimal and medial hypertrophyà vascular resistance

Micro: which arteries? Grading

§    Atheromas in large elastic arteries

§    Medial SM hypertrophy and intimal fibrosis in medium-sized muscular arteries and arterioles

§    Plexogenic arteriopathy[106]: only in primary HTN and some congenital cardiac defects

§    Secondary changes: COPD, organizing thrombi, diffuse pulmonary fibrosis

§    Grading or sequence of events (Leslie)[107][108]

1.  Muscular hypertrophy: in large arteries and arterioles

2.  Intimal proliferation

3.  Subintimal fibrosis (onion-skin)[109]

4.  Necrotizing vasculitis

5.  Plexiform lesions

6.  Dilatation and angiomatoid lesions: glomeruloid lesion attached to outside of arterioles

Gross[110]

§    PA atherosclerosis

§    Intracardiac shunts

§    PE

§    Right heart hypertrophy

§    Parenchymal infarct and pleural fibrinous exudate

Grading

§    ?

WHO and how

§    CP, SOB, hemoptysis, fatigue

Evolution

§    RHF (cor pulmonale)

§    Pneumonia

§    Severe respiratory failure (cyanosis)

Treatment

§    Vasodilators (calcium channel blockers, inhaled NO)

§    Anti-coagulation

§    Transplant

DIFFUSE PULMONARY HEMORRHAGE SYNDROMES

Name 3 conditions*

§    Goodpasture: necrotizing hemorrhagic interstitial pneumonitis, more in young men and smokers

§    Idiopathic pulmonary hemosiderosis: intermittent hemorrhage, responds to immunosuppression, prominent hemosiderin deposition with variable fibrosis

§    Vasculitis-related: HS angiitis, Wegener, SLE

§    Other: PE, microvascular injury (secondary to inhalants)

1. GOODPASTURE’S

§    Men[111], 20s, hemoptysis, smokers

Mechanism

§    HLA[112]à AB against noncollagenous domain of α-3 chain of collagen IV on GBM and alveolar BMà RPGN and necrotizing hemorrhagic interstitial pneumonitis (not vasculitis!)

Gross

§    Heavy + focal consolidation

Micro (lungs)

§    Early: focal necrosis of alveolar walls and intra-alveolar hemorrhage

§    Later: intra-alveolar organization, hemosiderin laden-macrophages, septal fibrosis, type II pneumocyte hypertrophy

Micro (kidney)

§    Early: focal proliferative GN or crescentic in RPGN

IF

§    Linear IgG and C3 in alveolar and glomerular BM

What has improved survival? Plasma exchange

 

2. IDIOPATHIC PULMONARY HEMOSIDEROSIS

Who and how?

§    Kids (adults much less common), insidious onset of intermittent hemoptysis, cough, anemia

§    No renal problem

Gross

§    Same as Goodpasture

Micro:

§    Intra-alveolar hemorrhage (acute or organizing)

§    Variable interstitial fibrosis

§    No: vasculitis, inflammation

Diagnosis

§    Of exclusion (must do IF to rule out Goodpasture and check serology for negative ANCA and no renal failure)

Evolution

§    Favorable with immunosuppression

3. VASCULTITIS ASSOCIATED HEMORRHAGE

DD for necrotizing granulomatous vasculitis***[113]

§    Wegener: with granulomas

§    Churg-Strauss: with granulomas

§    Bronchocentric granulomatosis (ABPA)

§    Rheumatoid nodule

§    Dirofilaria immitis: dog heartworm (self-limited in human)

CHURG-STRAUSS

Presentation

§    Asthmatic, fever, peripheral eosinophilia,

§    Lung, heart, skin, nervous system, GI

§    Either acute fulminant or chronic febrile[114]

Micro

§    Necrotizing granulomatous vasculitis by eosinophils[115]

§    Tissue eosinophilia

§    Eosinophilic pneumonia and eosinophilic vasculitis in lung

WEGENER’S GRANULOMATOSIS

Define

§    Pauci-immune vasculitis[116]

Presentation

§    Systemic vasculitis and granulomatosis can involve PNS, CNS, orbit, skin, ear, breast, other sites

§    Mid-aged, fever, cough, CP, hemoptysis

§    Limited form only affects lungs

Imaging

§    Bilateral and multiple cavitary nodules in lower lobes

Triad

§    Necrotizing granulomatous vasculitis

§    Aseptic necrosis of upper respiratory tract and lungs

§    RPGN

Lab

§    C-ANCA+[117] in 90%

Diagnosis

§    Biopsy of upper airway or skin

Micro

§    Vasculitis[118][119][120]: infiltration by PMN, eosinophils, plasma cells, +/-fibrinoid necrosis

§    Granulomas with geographic[121] necrosis[122]: surrounded by palisading MGC and histiocytes

§    Mixed acute and chronic inflammation including eosinophils

§    Use “consistent with”. Must rule out TB and fungi. Check serum c-ANCA

DD

§    Rheumatoid nodules: rounder granulomas, less prominent vasculitis, vasculitis located within granulomas, high rheumatoid factor

§    Churg-Strauss: peripheral eosinophilia, more eosinophils, no HN or kidney involvement

 

 

RHEUMATOID ARTHRITIS

Clinical

§

Forms of lung disease

§    Interstitial fibrosis

§    Rheumatoid nodules

§    Pleuritis with pleural effusion

§    Pulmonary vasculitis

§    Amyloidosis

§    Follicular bronchitis

§    LIP

Caplan syndrome

§    RA+CWP

MICROSCOPIC POLYARTERITIS MP

Define

§    Pauci-immune vasculitis

INFECTIONS

Defense mechanisms (3)

§    Nasal (cilia, swallowing, coughing)

§    Bronchial (cilia)

§    Alveolar (macrophages)

RF to infection* (5)

1.  No cough reflex (coma, anesthesia, drugs)

2.  Mucociliary loss (smoking, gases, viruses)

3.  Decreased phagocytosis (smoking, alcohol, O2)

4.  Edema (CHF)

5.  Excessive secretions (CF)

6.  Immunodeficiency (sickle, splenectomy)

 

Pneumonia syndromes (7)

1.  Community typical: Pneumococcus[123], Hi[124], Moraxella[125], Staph[126], Legionella[127], Klebsiella[128], Pseudomonas[129]

2.  Community atypical: Mycoplasma, Chlamydia, Coxiella, viruses

3.  Nosocomial[130]: Klebsiella, Pseudomonas, Staph

4.  Aspiration: anaerobic oral flora

5.  Chronic: Nocardia[131][132], Actinomyces, granulomatous (TB, Histoplasma, Blastomyces, Coccidioides)

6.  Necrotizing with abscess: anaerobic (no1), Staph, Klebsiella, Strep pyogenes, type 3 pneumococcus

7.  In immunocompromised: CMV, PCP, MAI, invasive aspergillus, invasive candida

How to date pneumonias?

§    Do not try to date pneumonia, especially in autopsy cases because no good study in literature

1. TYPICAL PNEUMONIA

2 gross distributions and bacteria associated with bacterial pneumoniae

§    Bronchopneumonia

Ø   Any germ listed under community typical pneumonia

Ø   Often multilobar at bases, 3-4cm patches, raised, palpable, not WC

§    Lobar pneumonia

Ø   Any community typical germs but mainly pneumococcus (95%)

Stages of uncomplicated lobar pneumonia[133] (4)*

1.  Congestion[134]: vascular congestion, edema, few PMN, lots of bacteria

2.  Red hepatization: exudate containing RBC and PMN

3.  Gray hepatization: fibrino-suppurative exudate persists after RBC disintegration

4.  Resolution: no scar

Complications of lobar pneumonia[135]*

§    Abscess

§    Empyema

§    Bacterial dissemination: meningitis, endocarditis, pericarditis, kidney abscess, splenic abscess, suppurative arthritis

§    Organization: air-filled becomes solid[136]

LEGIONELLA

§    Severe in immunocompromised

§    PMN

§    Leukocytoclastic vasculitis

§    Necrosis

§    Silver stainà G- bacilli

2. ATYPICAL PNEUMONIA

Atypical means what?

§    Moderate sputum, no physical findings of consolidation, only moderate leukocytosis, no alveolar exudate

Organisms

§    Mycoplasma

§    Viruses: influenza A,B, RSV, adenovirus, rhinovirus, VZV, CMV, HSV

§    Others

Ø   Chlamydia

Ø   Coxiella (Q fever)

Common mechanism

§    Epithelial necrosisà loss of mucociliary clearance

Micro*

§    Interstitial pneumonitis[137]

§    No intra-alveolar infiltrate but often hyaline membranes[138]

§    Some viruses[139] can be quite nasty by causing bronchial or bronchiolar epithelial necrosis whereas some cause cytopathic changes

Gross.

§    Patchy or lobar congestion[140] without consolidation[141]

INFLUENZA

Massive death by which mechanism?*

§    Epidemics: hemagglutinin and neuraminidase mutationsà antigen drift

§    Pandemics: hemagglutinin and neuraminidase replacement through RNA recombination with animal virusesà antigen shift

Does B and C mutate?

§    No[142]

Name a few diseases

§    Laryngotracheobronchitis

§    Bronchiolitisà cell debris and fibrinà organization into fibrous tissueà permanent obliteration of bronchioles in severe cases

§    Reye

§    URI (sinusitis, tonsillitis)

§    Myocarditis

§    Pneumonia

 

SARS

What’s special about this coronavirus strand?

§    Causes lower respiratory tracts unlike other coronaviruses

Micro

§    DAD with giant cells

Diagnosis

§    PCR

§    Serology (AB against virus)

§    EM

3. NOSOCOMIAL PNEUMONIA

§

PSEUDOMONAS

§

4. ASPIRATION PNEUMONIA

Why dangerous?

§    Often necrotizing and fulminant, leading to lung abscesses

Etio

§    Partly chemical (gastric) and partly mixed oral flora

5. CHRONIC PNEUMONIA

List commonalities between histoplasmosis, blastomycosis and coccidioidomycosis

§    Granulomatous reaction

§    Thermally dimorphic (hyphae producing spores in environmental temperature but yeasts in human)

§    Immunocompetent hosts

§    Geographically distributed

Ø   Histoplasma: Ohio, Mississippi rivers, Caribbean

 

Ø   Blastomyces: Central and Southeastern US, Canada

Ø   Coccidioides: Southwest or West US, Mexico

§    http://www.doctorfungus.org/

PRIMARY TUBERCULOSIS

Primary Pulmonary TB

What is the Ghon complex?

§    Subpleural lesion + enlarged caseating lymph nodes (draining the lesion)

Secondary (Reactivation) Pulmonary TB

Location, nodes

§    -apical solitary lesion which is reactivated + regional node involvement

§    -may cavitate and become fibrotic

Micro

§    -coalescent granulomas with fφ, lφ, GCs

Progressive Pulmonary TB

Name the 3 types

Cavitary Fibrocaseous TB

§    -cavity @ apex → caseous ctr. + fibrous wall

§    -dissemination by → blood, lymphatics→MILLIARY

§    OR LOCAL SPREAD

§    -pleura involved→ empyema, pleural effusions,

§    -lesions involve →endobronchial and endotrachea

Miliary TB (dissemination routes, organs most commonly affected, size of lesions, gross and micro)

§    -blood, lymphatics

§    -bone marrow, spleen, liver, retina

Bronchopneumonia TB

§    -bronchopneumonia secondary to TB in highly susceptible person

Name the different types of interstitial pneumonia

§    Primary Atypical Pneumonia

§    Hypersensitivity Pneumonitis

§    Idiopathic (UIP, NSIP, DIP)

§    Pneumoconioses

HISTOPLASMOSIS

How to contract it?

§    Inhale dust from soil contaminated by bird or bat droppings containing small spores (microconidia)

Where do you find bug?

§    Inside macrophages (obligate intracellular parasite)

Name different presentations (hint: similar to TB)

§    Self-limited: incidental coin lesions on CXR, often only mild symptoms

§    Chronic progressive: in apex, striking constitutional symptoms

§    Localized extrapulmonary:

§    Widely disseminated: in immunosuppressed

Can one be carrier?

§    ?

Mechanism

§    Internalized into macrophages after opsonizationà multiplication inside inactivated macrophagesà burst out by killing macrophages

§    Infection controlled by T cells by activating macrophages

Gross

§    Fibrosis and laminated concentric calcification (often subpleural with pleural retraction) when chronic or treated (tree-bark appearance), less cavitating than TB

Micro*

§    Same as TB with granulomas with coagulative necrosis[143]

§    Diagnosis requires 3-5μm thin-walled yeast[144]

Can it bud?

§    ?

What’s special about micro of disseminated form?*

§    Focal accumulations of mononuclear phagocytes filled with fungal yeasts[145]

§    No granulomas because no epithelioid histiocytes (lack of activation)

 

How to diagnose?

§    Usual tests: culture, histology, serology

BLASTOMYCOSIS

What?

§    Soil-inhabiting dimorphic fungus, remarkably difficult to culture

Forms (3)

§    Pulmonary: usual TB symptoms, miliary-looking on CXR, mainly upper lobes

§    Disseminated

§    Cutaneous: rare

Micro

§    Suppurative granulomas in normal hosts

§    5-15μm[146] round thick-walled yeasts, broad[147]-based budding, one to multiple nuclei[148]

§    Lots of PMN because fungi not killed by macrophages

§    Outside macrophages?

 

What one must be careful with skin or mucosal infection?*

§    Cause marked epithelial hyperplasia, mistaken for SCC

COCCIDIOIDOMYCOSIS

Where?

§    Spores from soil

§    Endemic in Southwest and Western US (80%)

SSx?

§    Mild presentation like histoplasmosisà only 10% symptomatic

Mechanism

§    Ingestion by alveolar macrophagesà block fusion of phagosome and lysosomeà no killing

Evolution?

§    <1% become disseminated to skin and meninges

Micro

§    From pus[149][150] to granulomas[151]

 

ASPERGILLOSIS

Fungus***

§    Ubiquitous

§    Can cause allergy or colonize healthy but cause severe sinusitis, pneumonia and disseminated disease in immunocompromised

§    Aflatoxin in peanutsà cancer

Forms of disease in lung***

§    ABPA: allergic reaction to Aspergillus in asthmatics

§    Aspergilloma: colonization of pre-existing cavity, no invasion

§    Invasive: opportunistic in immunosuppressed, necrotizing pneumonia with sharp hemorrhagic borders (target lesions)

Micro of invasive and non-invasive

§    Invasive: septate hyphae, acute angle, spore-producing fruiting bodies if O2, vascular thrombosis, hemorrhage and infarct, necrosis

§    Non-invasive:

6. NECROTIZING PNEUMONIA

LUNG ABSCESS

Definition

§    Suppurative process + lung tissue necrosis

Name a few organisms causing abscesses[152]

§    Staph

§    Streptococcus pyogens

§    Anaerobes[153]: Bacteroides, Fusobacterium, Peptococcus

§    Gram negative

Causes of lung abscess (5) and location*

§    Aspiration[154] (no1): ENT surgery, sinobronchial infections, dental abscesses, bronchiectasis, loss of consciousness (anesthesia, acute alcoholism, gastric juice[155], seizures)

§    Prior pneumonia

§    Septic embolism

§    Obstruction: cancer

§    Direct wound: trauma

§    Spread from other organs

Number of abscess may be helpful[156]

§    Single: aspiration, post-obstructive

§    Multiple: prior pneumonia, embolic

Micro*

§    Fibrous wall if chronic

Who and how?

§    Foul-smelling cough, fever, weight loss, clubbing after a few weeks

Treatment: requires drainage?

§    No

Complications*

§    Meningitis

§    Brain abscesses

§    AA amyloidosis

7. PNEUMONIA IN IMMUNOCOMPROMISED

Distribution of infiltrate?

§    Robbins 756

Name a few*

§    Viruses: CMV, HSV

§    Bacteria: Pseudomonas, Mycobacterium, Legionella, Listeria

§    Fungi: PCP, Candida, Aspergillus, Cryptococcus

Infections in relation with CD4 levels*

§    >200cells/mm3: bacterial and mycobacterial

§    <200: PCP

§    <50: CMV, MAI

 

PCP

§    Opportunistic fungus

§    CD4 <200

§    Diffuse or patchy pneumonia

Diagnosis

§    BAL

Micro

§    Pink, frothy, amorphous material composed of proliferating fungi and cell debris

§    4-6µm, cup/boat shaped cysts

§    Any silver stains

DDx

§    Alveolar proteinosis: PAS+, no inflammation

§    Goodpasture’s: necrotizing hemorrhagic interstitial pneumonitis, associated with RPGN, IF

 

 

 

 

CRYPTOCOCCUS

 

 

CANDIDA

 

 

LISTERIA

 

 

ASPERGILLUS

 

 

DRUG-INDUCED

 

 

DIROFILARIASIS

 

LUNG TRANSPLANT

Common indications

§    COPD

§    UIP

§    CF

§    Primary pulmonary HTN

Usually 1 lung except when?

§    Except bilaterally infected lungs such as CF and bronchiectasis

2 common complications

§    Infections (same as those in immunosuppressed)

§    Rejection

Micro for rejection*

§    Acute (weeks or months): vascular and airway inflammation[157]

§    Chronic (3-5 years): bronchiolitis obliterans[158]

Treatment

§    CTSD good against acute cellular rejection but not good when it’s chronic (BO phase)

 

 

TUMOURS

Classify lung epithelial cancers***

§    SCC (25-40%)

§    Adenocarcinoma (25-40%)

Ø   Acinar, papillary, bronchioloalveolar, solidà STP pattern again!

Ø   Mixed with SCC (quite common)

§    Small cell NE carcinoma

Ø   Combined with SCC, large cell NE carcinoma or sarcoma

§    Large cell undifferentiated carcinoma

Ø   Large cell NE carcinoma

§    Carcinoids

Ø   Typical, atypical

§    Carcinomas of salivary gland type

§    Unclassified

Classify non-epithelial tumors

§    IMT

§    Fibroma

§    FS

§    LAM

§    LM

§    LMS

§    Lipoma

§    Hemangioma

§    HPC/solitary fibrous tumor

§    Chondroma

§    Lymphoma

Ø   Langerhans cell histiocytosis

Ø   HD

Ø   Lymphomatoid granulomatosis (diffuse large B and T lymphomas)

Ø   Maltoma

§    Mets

RF

§    Smoking[159][160] (10-60x)

§    Radiation

Ø   Uranium (4x)

Ø   Radon

§    Heavy metals (beryllium, arsenic, chromium, Ni, Fe)

§    Asbestos (5x)

§    Air pollution

Degree of association with smoking

§    Small cell, SCC> large cell> adenocarcinoma> BAC?>carcinoids (60-80%)

Can stop smoking reduce risk?

§    Yes, must stop for >10 years and never back to normal level

How cigarettes cause cancer?

§    Initiators: polycyclic aromatic hydrocarbons such as benzopyrene

§    Promoters: phenol derivatives

Cancers associated with smoking*

§    Lung

§    Mouth

§    Pharynx

§    Larynx

§    Esophagus

§    Pancreas

§    Cervix

§    Kidney

§    Bladder

Oncogenes in bronchogenic carcinomas?***

§    Small cell carcinomas: c-myc, RB

§    Non-small cell carcinomas: k-ras[161], p16

§    Both: p53

§    Others: EGFR[162], HER2, loss of 3p[163] (important)

§    Cytochrome P450 polymorphism: CYP1A1 higher risk[164]

Precursor lesions

§    Squamous dysplasia and CIS

§    Atypical adenomatous HP

§    Diffuse idiopathic pulmonary NE cell HP

Carcinogenesis sequence

§    Squamous dysplasiaà CISà SCC

Origin of cancers

§    Adenocarcinoma and BAC: alveolar septa and terminal bronchioles

§    SCC, small cell carcinoma: 1^st to 3^rd order bronchi

Pathways of spread? Name common sites

§    Both lymphatic and hematogenous[165]

§    Adrenals (no1, 50%), liver (50%), brain (20%), bone (20%)

Paraneoplastic hormones implicated in bronchogenic carcinomas***

§    ACTHà SCLC[166]

§    ADHà SCLC

§    PTH-related peptide or prostaglandin Eà hyperCaà SCC

§    Calcitoninà hypoCa

§    Gonadotropinsà gynecomastia

§    Serotonin in carcinoids

§    Others

Ø   Lambert-Eaton syndrome: myasthenia (AB towards neuronal calcium channel)à SCLC

Ø   Sensory[167] peripheral neuropathy

Ø   Acanthosis nigrans

Ø   Leukemoid reactions

Ø   Hypertrophic pulmonary osteoarthropathy: clubbing

Secondary changes*

§    Focal emphysema if partial obstruction*

§    Atelectasis if total obstruction*

§    Severe suppurative or ulcerative bronchitis or bronchiectasis

§    Lipid pneumonia: tumor obstructionà accumulation of cellular lipid in foamy macrophages

§    Hoarseness: recurrent laryngeal nerve invasion

§    Dysphagia: esophageal invasion

§    Diaphragm paralysis: phrenic nerve invasion

§    Horner syndrome: sympathetic ganglia invasion

§    Pulmonary abscesses

§    SVC syndrome

§    Pericarditis

§    Pleuritis

SVC syndrome?

§    Dusky head (plethora), arm edemaà death by circulatory compromise

Horner syndrome by Pancoast tumors*. Which side?

§    Enophthalmos, ptosis, miosis, anhidrosis on same side

Grading: worst area or overall grading?

§    Worst area

Prognosis

§    Staging: pleural effusion

§    Weight loss >10%

§    Young <40yo

§    LVI

§    No host inflammatory response

§    Small cell or giant cell variants

How to diagnose non-NE-looking but NE marker+ tumors?

§    Either ignore NE result or diagnose as tumor with NE features

1. BENIGN EPITHELIAL TUMORS

Types (WHO)

§    Papilloma

Ø   Squamous[168]: due to HPV

Ø   Glandular

Ø   Mixed

§    Adenoma

Ø   Alveolar

Ø   Papillary

Ø   Of the salivary gland type

Ø   Mucinous cystadenoma

2. PREINVASIVE LESIONS

1. CIS

§    Diagnosis requires expert confirmation

2. ATYPICAL ADENOMATOUS HP

§    <5mm

§    Less stratification

DD

§    BAC: more stratification, >1cm usually

3. DIFFUSE IDIOPATHIC PULMONARY NE HYPERPLASIA

 

MALIGNANT EPITHELIAL TUMORS

Types (WHO)

§    SCC

Ø   Papillary

Ø   Clear cell

Ø   Small cell

Ø   Basaloid

§    Small cell

Ø   Combined

§    Adenocarcinoma

Ø   Mixed

Ø   Acinar

Ø   Papillary

Ø   BAC

§    Nonmucinous

§    Mucinous

§    Mixed

Ø   Solid with mucin production

§    Fetal adenocarcinoma

§    Mucinous carcinoma

§    Mucinous cystadenocarcinoma

§    Signet-ring cell

§    Clear cell

§    Large cell

Ø   Large cell NE

§    Combined

Ø   Basaloid

Ø   Lymphoepithelioma-like

Ø   Clear cell

Ø   With rhabdoid features

§    Adenosquamous

§    Sarcomatoid

Ø   Pleomorphic carcinoma

Ø   Spindle cell

Ø   Giant cell

Ø   Carcinosarcoma

Ø   Pulmonary blastoma

§    Carcinoid

Ø   Typical

Ø   Atypical

§    Salivary gland tumors

Ø   MEC

Ø   AdCC

Ø   Epithelial-myoepithelial carcinoma

§    Preinvasive

Ø   CIS

Ø   Atypical adenomatous HP

Ø   Diffuse idiopathic pulmonary NE cell HP

1. SCC

Associations: any viral association?

§    HPV (up to 20% of cases)

Paraneoplastic syndrome: name most common

§    HyperPTH (no1)

EM

§    Tonofilaments and desmosomes

Micro

§    Need to identify keratin pearls or intracellular bridges

§    Cavitation with necrosis

§    May be associated with adjacent squamous cell metaplasia or carcinoma in situ

§    Can have MNG (non-neoplastic)

Variants 4

§    Basaloid[169]

Ø   Peripheral palisading, darker blue nuclei, no nucleoli, no nuclear molding, less cytoplasm

Ø   Central squamous differentiation

Ø   Anastomosing trabeculae with frequent microcystic space.

Ø   TTF1-: useful vs large cell NE carcinoma

§    Small cell

Ø   Small tumor cells with focal keratinization, distinct nucleoli, sharply outlined tumor nests, less necrosis than small cell NE carcinoma

§    Clear cell: clear cells containing glycogen

§    Papillary

§    Spindle cell: not in WHO

Genetics

§    Highest p53 mutation rate[170] in 90%

§    RB loss in 15%

§    P16 loss in 65%

§    3p loss

§    EGFR over expression in 80%

§    HER2 over expression[171] in 30%

IHC

§    CK+

§    HMK+: 34βE12, CK5/6,

§    TTF1-

§    CK7-/20-

§    P63+ (97%)[172]

 

1a. PAPILLARY

1b. CLEAR CELL

1c. SMALL CELL

1d. BASALOID

Basaloid SCC vs small and large cell NE carcinoma

Basaloid SCC	Small/Large cell NE
HMK+	TTF1+
	NE markers+

2. SMALL CELL NE CARCINOMA

Gross

§    Central but occasionally peripheral

§    White, friable, necrotic

EM

§    Dense-core membrane-bound granules (100-200nm)

Locations

§    Lung, nasal cavity, sinuses, breast, cervix, bladder, prostate, GI, pancreas, thyroid, adrenal, skin (Merkel cell), salivary glands (Archives)

Micro

§    Small, round cells, ↑↑N/C

§    Nuclei can be oval or spindly

§    Dark, no nucleoli, Azzopardi effect (DNA encrustation from necrotic tumor cells to BV walls)

§    Minimal cytoplasm

§    Salt and pepper[173] without prominent clumps

§    Osler says nuclear size not that different from large cell NE carcinoma but has much less cytoplasm

§    Nuclei 2-4x PMN size

§    Necrosis, apoptosis

§    Indistinct borders

§    Minimal stroma but vascular

§    Molding, smudging,

§    No squamous or glandular differentiation

§    Can mix with large cell NE or NSCLC

 

Is diagnosis based on morphology or IHC?

§    Morphology (therefore can be NE markers-)

Should you grade?

§    No

Paraneoplastic syndromes

§    ADH (hyponatremia), ACTH (Cushing’s syndrome), parathyroid hormone (hyperparathyroidism), calcitonin (hypocalcemia), gonadotropins (gynecomastia), serotonin (carcinoid syndrome), encephalomyelitis, sensory neuropathy, Lambert-Eaton syndrome

Name one variant

§    Combine: with other types such as larger cell NE carcinoma or sarcoma

EM: size of neurosecretory granules

§    100-200nm

Hormones secreted?

§    Chromogranin

§    Synaptophysin

§    Leu7

§    PTH-like

Genetics*

§    RB: 80-100%

§    P53: 50-80%

IHC[174]

§    CK20 dot+

§    CK7-

§    NE markers+: requires >20% of positive cells for true positivity. Includes NCAM (CD56), NSE, Cg, Syn

§    TTF-1+[175]

§    BCL2+ in 90%

§    S100+ (Archives, Steinberg) but Dabbs says negative

§    VIM?

§    C-kit+

§    Quite highly+ for mesothelial markers…

§    NF-: useful vs neuroblastoma because both NE markers+

Survival compared to other NE tumors

§    Typical carcinoid> atypical carcinoid> large cell NE carcinoma> small cell NE carcinoma

Treatment

§    Chemoradiation

§    Surgery if very localized

DD

§    Large cell NE carcinoma: vesicular nuclei, visible nucleoli, more cytoplasm, large nuclei

§    Atypical carcinoid: less atypia, <20/10, no extensive necrosis, more intensive NE staining

2a. COMBINED SMALL CELL CARCINOMA

3. ADENOCARCINOMA

Clinical

§    More peripheral and smaller

§    No1 in women and non-smokers

Define*

§    Gland formation or mucin production

Variants (hint: STP)

§    Mixed

§    Solid with mucin production[176]

Ø   Signet ring

Ø   Mucinous

Ø   Clear cell

Ø   Fetal

§    Acinar (tubular)

§    Papillary

§    BAC

Ø   Mucinous

Ø   Non-mucinous

§    Not in WHO

Ø   Terminal respiratory TRU[177]

§    Subset of adenocarcinomas with distinct clinico-pathologic features

• East Asia, with BAC features, females, Asians, nonsmokers, indolent, diffuse involvement (vs more pneumonic consolidation of most NSCLC), good response to EGFR inhibitor (Lit).
• EGFR mutation frequent, TTF1+, surfactant protein expression

§    Lobectomy could be curative but with frequent lung-only recurrences (Lit). Therefore, lung transplantation may be promising (Lit).

§    Originated from Clara cells, type II pneumocytes and non-ciliated bronchiolar cells (Lit).

Genetics

§    K-ras mainly

§    P16, RB, p53 similar to SCC

Micro

§    Acinar in center with BAC in periphery[178]

§    Mixed (signet-ring, clear cell)

§    Often contain mucin + tubular OR papillary pattern

IHC

§    CK+

§    TTF-1+: decreases with increase in grade

§    Calretinin+ in 10%

§    CK20- but + in 10%

3a. MIXED

3b. ACINAR

3c. PAPILLARY

3d. BRONCHIOLOALVEOLAR CARCINOMA

Link with smoking?

§    Usually not associated or less associated

§    M=F

Gross

§    Non-mucinous BAC[179]: single peripheral[180] nodule[181]à favorable because resectable

§    Mucinous BAC[182]: multiple diffuse nodules coalescing into pneumonia-like consolidationà dismal

Micro

§    No stormal, vascular or pleural invasion

§    Lepidic everywhere[183], sometimes with papillary projections

§    Diagnosis only on resection specimen (Lit)

Genetics

§    EGFR mutation (Lester)

Carcinogenesis sequence*

§    Atypical adenomatous HP[184] (adenoma?)à BAC

Variants

§    Mucinous: tall columnar with obvious intracytoplasmic mucin, on bronchioles (not bronchi), sharp demarcation with normal

§    Non-mucinous: columnar-cuboidal cells, bright eosinophilic cytoplasm, nucleoli, hobnail cells or apical spouts, psammoma in 10%, PAS+ intranuclear inclusions

 

 

EM

§    Mucinous: bronchiolar goblet cells

§    Non-mucinous: Clara cells or pneumocytes II

Prognosis*

§    Non-mucinous because often solitary peripheral nodule with rare aerogenous spreadà amenable to resection

§    Localized disease

Treatment

§    Possible ude of Iressa

IHC

§    TTF1: + in non-mucinous but – in mucinous

§    CK7+/CK20- but CK20+ in 25-90% of mucinous[185] (Outlines)

§    Surfactant[186] and A1AT[187]+: in non-mucinous

Evolution

§    Not all BAC evolve towards invasion even left untreated

§    By definition non-invasive[188], kill by suffocation*

3e. SOLID WITH MUCINOUS PRODUCTION

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4. LARGE CELL CARCINOMA

Micro[189]

§    Large round to vesicular nuclei

§    Prominent nucleoli

§    Moderate cytoplasm (high N/C)

§    Indistinct cell border (WHO)

§    No glandular (mucin droplets) or squamous differentiation by definition[190]

§    Diagnosis of exclusionà don’t diagnose on small biopsies or in LN metastases

 

Association with smoking?

§    Strong except epithelioma-like variant

Location

§    All peripheral except basaloid (WHO)

EM

§    Minimal squamous[191] or glandular[192] differentiation often still visible

IHC

§    TTF1: variable results[193]

§    Seems to have higher chance of mesothelial markers+ such as CK5+ (50%), calretinin+ (35%), thrombomodulin+ (25%)

Grading: should one grade?

§    PD by definition (WHO)

Variants[194]

§    Basaloid

§    Large cell NE carcinoma

Ø   Combined[195]

§    With rhabdoid feature

§    Lymphoepithelioma-like

§    Clear cell

Basaloid carcinoma vs large cell NE carcinoma (Archives)[196]

Basaloid	NE
No	NE markers+
No	TTF1+ in 50%
HMK+	No

 

4a. LARGE CELL NE CARCINOMA[197]

Micro: 5 diagnostic criteria

§    NE architectures such as organoid nesting, trabecular growth, rosettes, palisading

§    Larger cells with moderate-abundant cytoplasm

§    ≥11/2mm²=≥11/10HPF

§    Large necrosis

§    Prominent nucleoli

§    Nuclei >3x lymphocyte size

§    At least one NE marker+[198]

Patterns

§    Nests, trabecular, rosette-like, palisading

Genetics

§    Same as small cell NE carcinoma

Treatment

§    Controversial: some treat it as NSCLC and some as SCLC

4b. BASALOID CARCINOMA

4c. LYMPHOEPITHELIOMA-LIKE

4d. CLEAR CELL

 

4e. LARGE CELL WITH RHABDOID PHENOTYPE

5. ADENOSQUAMOUS CARCINOMA

 

6. SARCOMATOID CARCINOMA

6a. PLEOMORPHIC

6b. SPINDLE CELL

6c. GIANT CELL

6e. CARCINOSARCOMA

§    Considered as carcinomas with sarcomatoid diff. by some

Micro

§    Usu squamous cells + sarcomatous component (MFH, FS, etc.)

6f. PULMONARY BLASTOMA

Define***

§    Specific variant of carcinosarcoma

§    Biphasic tumor containing primitive epithelial component that may resemble WD fetal adenocarcinoma and primitive mesenchymal stroma with occasional heterologous elements (OS, CS, RMS)

Clinical

§    Adults, peripheral, solitary

Genetics: new discovery

§    B-catenin mutation

Origin

§    Considered subtype of pleomorphic carcinoma or carcinosarcoma

Micro***

§    Biphasic tumor consisting of

Ø   Malignant glands resembling fetal tubules[199]

Ø   Undifferentiated blastema-like stroma

Ø   Sometimes muscle/cartilage differentiation

§    Cytoplasmic vacuoles (glycogen)

§    May be difficult to separate from carcinosarcoma

 

Outcome

§    Very aggressive

IHC***: which cells

§    Epithelial cells

Ø   Epithelial markers+ (CK, EMA, CEA): in epithelial component

Ø   PAS+ for glycogen

§    Stromal cells

Ø   VIM+

Ø   SMA+

DD

§    Fetal adenocarcinoma: no blastemal stroma

7. NEUROENDOCRINE TUMOURS

Etiology

§    Kulchitsky cells

Name the different types:

§    Typical carcinoid

§    Atypical carcinoid

§    Peripheral carcinoid

§    Tumorlet

§    Others:

Ø   Small cell carcinoma

Ø   Large cell neuroendocrine carcinoma

Ø   Non-small ca. cell with NE differentiation

 

7a. TUMORLET

Nature

§    Benign (hyperplasia vs neoplasia debatable)

Where?

§    Scar (in particular bronchiectasis) or chronic inflammation

Micro

§    Defined as <0.5cm (arbitrary dividing point)

§    Near bronchioles

DDx

§    Minute meningothelial-like nodules: not related to air spaces but situated within interstitium, generally near septal veins. Lacks NE features

7b. CARCINOID

Clinical: any syndrome?

§    <40[200]. M=F.

§    Some with carcinoid syndrome (intermittent attacks of flushing, diarrhea, cyanosis)

§    Some with MEN1

Location

§    Central: endobronchial collar-button lesions

§    Peripheral (rare): nodules

Who?

§    Younger than 40, equal gender

RF: smoking relationship?

§    20-40% are non-smokers (basically no)

Gross

§    Endobronchial

§    Yellow, no necrosis

§    Atelectasis

Mets: characteristic of bony mets?

§    Osteoblastic

Micro: what patterns (4), what no?

§    Nests, trabeculae/cords, rosette/acini, mucinous (goblet), solid, papillary

§    Delicate FV septa

§    Uniform small round to oval[201] central nuclei[202], moderate eosinophilic granular cytoplasm

§    Sometimes amyloid

§    No: necrosis, mitoses, crushing artifact

IHC[203]

§    CK+ (dot-like[204])

§    NE markers+: stronger than in SCLC

§    TTF1+ in 50%

§    Various peptide hormones or enzymes

§    NF+ (Rosai)à not sure about this…

§    CK7+/CK20-

§    S100+ in sustentacular cells only

§    BCL2+ but less than in SCLC

EM: size and location

§    Membrane-bound electron-dense neurosecretory granules 100-400nm

Carcinoid vs paraganglioma

Carcinoid	Paraganglioma
Sustentacular cells (S100+)
CK dot+	CK-
NE markers+

 

7c. ATYPICAL CARCINOID

 

8. SALIVARY GLAND TUMORS

Variants

§    AdCC

§    MEC

§    Epithelial-myoepithelial carcinoma

8a. AdCC

Incidence

§    No1 SG tumor in lung; MEC no2 (Steinberg)

Outcome

§    Poor because multiple local and metastatic recurrencesà prolonged death

Locations

§    Endobronchial in major bronchi

8b. MEC

Locations

§    Endobronchial in major bronchi

Micro

§    Must grade

§    Mixed of mucus-secreting, squamous and intermediate cells

Prognosis

§    Good

DDx

§    Adenosquamous

8c. EPITHELIAL-MYOEPITHELIAL CARCINOMA

MESENCHYMAL

Variants (WHO)

§    Epithelioid HE

§    Angiosarcoma

§    Pleuropulmonary blastoma

§    Chondroma

§    LAM

§    IMT

§    SS

§    Pulmonary artery or vein sarcoma

1. EPITHELIOID HE

2. ANGIOSARCOMA

3. PLEUROPULMONARY BLASTOMA

4. CHONDROMA

6. LYMPHANGIOMATOSIS (LAM)

Clinical

§    Only in women, white, reproductive

§    Wheezing, SOB, pneumothorax or emphysema even without smoking history

§    Tuberous sclerosis

§    Worsened by pregnancy or menstruation

Micro

§    Cystic airspaces

§    SM proliferation[205] in interstitium and “spin off” of bronchi, veins, lymphatics

§    Prominent lymphatics in pleura and alveolar septa

§    Cysts are often collapsed

§    Numerous hemosiderin laden macrophages and RBCs

IHC: HMB45, ER, PR

Prognosis: poor, lead to cor pulmonale

 

7. INFLAMMATORY MYOFIBROBLASTIC TUMOR***

Clinical

§    <30 yo [206]

Gross

§    WC, pale yellow, homogeneous

Micro

§    Proliferation of MFB and FB

§    Lymphocytes, plasma cells[207], foamy histiocytes[208]

§    Peripheral fibrosis

§    Can resemble nodular fasciitis, dermatofibroma or fibromatosis

IHC

§    VIM+

§    SMA+

DD

§    Carcinosarcoma

§    Sarcomatoid carcinoma

§    Mesenchymal tumours

§    Sarcomatoid mesothelioma

8. SS

9. PULMONARY ARTERY OR VEIN SARCOMA

METS

Locations compared to primary?

§    Mets more peripheral, multiple (cannonball)

Metastatic vs primary

§    Mets: multiple, bilateral, sharp outline, rapid growth, more pleomorphic and necrotic, TTF1-, lymphangitis carcinomatosa

Origins by patterns (nodules, lymphangitic, cavitary)

§    Nodules: breast, GI, kidney, sarcoma, melanoma

§    Lymphangitic: stomach, breast, choriocarcinoma, pancreas, prostate

§    Cavitary: SCC of upper aerodigestive tract, colon, LMS

§    Intrabronchial: breast, kidney, colon

§    Tumor emboli[209]: breast, stomach, liver, choriocarcinoma

§    Lepidic: colon, pancreas!

§    Pneumonic consolidation

 

LYMPHOPROLIFERATIVE DISORDERS

§    Benign

§    Lymphoid interstitial pneumonia

§    Malignant

§    BALT (low grade)

§    Lymphomatoid granulomatosis (high grade)

§    -mult. nodules

§    -angio-centric/invasive/destructive

§    Hodgkin disease

LYMPHOMATOID GRANULOMATOSIS

§    EBV+, LYMPHOMA, looks like granuloma,

Aka?

§    T-cell rich B-cell lymphoma, angiocentric lymphoma

Etio

§    EBV***

Micro[210]

§    Nodules of necrosis with ghost-like vessels within necrotic zones

§    Atypical enlarged cells bordering necrosis admixed with small reactive T-cells

LYMPHOMA

Incidence

§    Maltoma> intravascular DLBCL

Micro

§    Expands interstitium, not intra-alveolar (Boag)

§    Classic appearance: nodules with extension along lymphatic routes (bronchovascular bundles, intralobular septa and pleura) (Osler).

PLASMACYTOMA

RARE SARCOMAS

§    LMS

§    RMS

§    Epithelioid HE

MISCELLANEOUS

Types (WHO)

§    Hamartoma

§    GCT

§    Melanoma

§    Intrapulmonary thymoma

§    Sclerosing hemangioma

§    Sugar cell tumor: good prognosis,

 

Not included in WHO

§    Minute meningothelial-like nodule

§    Tumorlet

1. HAMARTOMA[211]

Clinical: older adults

How is it called on imaging?

§    Coin lesion with popcorn calcification

Syndrome

§    Carney’s triad

Nature: acquired or congenital?

§    Acquired. Some evidence suggesting neoplastic (clonal, not congenital)

Micro[212]

§    Cartilage

§    Fat

§    Spaces lined by respiratory epithelium

§    BV

 

2. SCLEROSING HEMANGIOMA (misnomer)

Clinical

§    Adult females, mid-aged, incidental finding of coin lesion on imaging

Origin

§    Type II pneumocytes[213]

Gross

§    WC, solid, tan

§    Easily “shelled out”

Micro (hint: 2 components)

§    Epithelial (polygonal)à CK, CD15, EMA

Ø   Bland polygonal cells cells with abundant eosinophilic cytoplasm, no nucleoli

§    Round stromal cellsà TTF-1 (neg for above)

§    WC and encapsulated (Osler)

§    Zonation

Ø   Papillary at periphery, lined by cuboidal cells

Ø   Angiomatous or solid center formed by medium-sized pale polygonal cells with clear cytoplasm

 

 

 

 

 

Prognosis

§    Benign, slow-growing

Treatment

§    Easily shelled out

IHC

§    TTF1+

§    Surfactant+

§    ER+

§    PR+

§    Vascular markers-

 

 

3. SUGAR CELL TUMOR

4. GCT

5. INTRAPULMONARY THYMOMA

6. MELANOMA

MINUTE MENINGOTHELIAL-LIKE NODULE MMN[214]

Incidence

§    Common and multiple (Web).

Clinical

§    5x more in F

Origin

§    Meningothelial[215] rather than chemoreceptor cell origin

Location

§    Minute (2mm) subpleural nodules

Prognosis

§    Asymptomatic

§    Unknown clinical significance

Micro

§    Uniform, epithelioid/spindle cells containing round to oval nuclei devoid of atypia and moderate to abundant amount of eosinophilic cytoplasm

§    Forms nests around small veins within interstitium (therefore widens alveolar septa) and radiate centrifugally in a stellate fashion

IHC

§    EMA+

§    VIM+

§    CK-

§    S100-

§    NE markers-

 

PLEURA

NORMAL

Amount of fluid

§    15cc, relatively acellular

Normal mesothelials

§    LWK+, HWK+

§    Resting mesothelium composed of flat, tightly connected cells, no more than 1 layer thick

Subpleural FB

§    VIM+, CK- (+ when reactive)

§    Responsible for regeneration of mesothelial lining

Mesothelial cells in LN

§    Can be normal (in nodal sinus)!

Pearls

§    Some SM fibers within pleura is normal (Dexter)

§    Not confuse hypertrophic submucosal glands in COPD patient with invasive adenocarcinoma

PLEURAL EFFUSIONS*

Types

§    Inflammatory

Ø   Serofibrinous: TB, pneumonia, infarcts, abscesses, RA, uremia

Ø   Suppurative (empyema)

Ø   Hemorrhagic[216]: coagulation disorders, rickettsia, neoplasm

§    Non-inflammatory[217]

Ø   Hydrothorax[218]

§    Increased hydrostatic: CHF

§    Increased permeability: pneumonia

§    Decreased oncocytic: nephrotic

§    Increased pleural negative pressure: atelectasis

§    Decreased lymphatic drainage: carcinomatosis

Ø   Hemothorax[219]: rupture aortic aneurysm, vascular trauma

Ø   Chylothorax

PNEUMOTHORAX

3 most common causes*

§    TB

§    Emphysema

§    Asthma

MESOTHELIAL TUMORS

Types (WHO)

§    Diffuse MM

Ø   Epithelioid

Ø   Sarcomatoid

Ø   Desmoplastic

Ø   Biphasic

§    Localized MM

§    WD papillary mesothelioma

§    Adenomatoid tumor

ATYPICAL MESOTHELIAL HP

Micro

§    Single layer of hyperchromatic, discrete mesothelial cells, often forming picket fence arrangement

1. DIFFUSE MESOTHELIOMA

Clinical

§    50-80, 3x more males, SOB, nonproductive cough, recurrent effusion, asbestosis exposure for >15yrs[220] between 15-60yrs ago

§    Rarely paraneoplastic hypoglycemia (insulin-like substance)

Diagnosis (USCAP)

§    Detailed clinical history

§    Detailed radiologic information

§    Adequate biopsy material

§    IHC

§    EM

Diagnosis: what methods?

§    Cytology diagnostic in 1/3

§    Open lung biopsy diagnostic in ≈100%

Variants***

§    Epithelioid (no1)

Ø   Tubulopapillary[221]

Ø   Solid

Ø   Adenomatoid

Ø   Deciduoid

Ø   Clear cell

Ø   Glandular

Ø   Myxoid

§    Sarcomatoid (no3): resembles FS, heterologous differentiation rare but possible

§    Desmoplastic

Ø   Anaplastic: extreme atypia

§    Mixed (no2): epithelioid mixed with spindle[222]

§    Not in WHO

Ø   Rhabdoid[223] (new): significant because aggressive

Micro

§    Epithelioid

Ø   Cuboidal or flat cells forming STP patterns!

Ø   Round nuclei with nucleoli, fuzzy borders (microvilli)

Ø   Psammomas rare

§    Sarcomatoid

§    Desmoplastic[224]

Ø   Bland and collagenized

Ø   Very difficult diagnosisà look for necrosis, atypia, mitoses and invasion!

Does mesothelioma in situ exist?

§    Yes but rare. Looks like CIS of bladder with hobnailing and clinging pattern. Cautious with this diagnosis

Do they commonly have asbestosis (interstitial fibrosis)?

§    No, only 20% have concomitant interstitial fibrosis

Clinical

§    History of asbestos[225] exposure

Gross

§    Multiple white nodules in a diffusely thickened pleura (unlikely to have intraparenchymal masses)

§    Serous effusion

Micro

§    STP[226][227] patterns

§    Cytology: uniform, cuboidal (adenoca is usu. columnar)

Grading

§    Not done

Spread

§    Hilar LNà liverà elsewhere (adrenals, contralateral pleura

§    Less commonly lymphangitic spread in lung, pulmonary alveolar permeation through pore of Kohn and lepidic intrapulmonary growth (Leslie).

RF (USCAP) [228]

§    Asbestos[229]

§    Radiation

§    Chronic inflammation

§    Viral infection

§    DES

IHC[230][231][232]

§    CK+

§    EMA+

§    VIM- in epithelioid but + in sarcomatoid

Genetics

§    Characteristic 9[233] and 22[234] deletions (Lester)

Prognosis: bad***

§    Stage

§    Males bad

§    Old bad

§    Sarcomatoid worse than biphasic than epithelioid

Asbestosis patients will much more likely to die from which cancer?*

§    20% lung cancer, 10% mesothelioma, 10% GI carcinomas!

Treatment*

§    Extrapleural pneumonectomy[235] in young

 

2. LOCALIZED MESOTHELIOMA

 

3. WD PAPILLARY MESOTHELIOMA

Define

§    Rare (50 cases reported in pleura) but much more common in peritoneum

§    More in women

§    Bland papillary tumor with tendency for superficial spread but no invasion (or just superficial?)

§    Malignant

4. ADENOMATOID TUMOR

 

LYMPHOPROLIFERATIVE

Types (WHO)

§    Primary effusion lymphoma

§    Pyothorax-associated lymphoma

1. PRIMARY EFFUSION LYMPHOMA

 

2. PYOTHORAX-ASSOCIATED LYMPHOMA

 

MESENCHYMAL

Types (WHO)

§    Epithelioid HE

§    Angiosarcoma

§    SS

§    SFT

§    Calcifying tumor of pleura

§    DSRCT

1. EPITHELIOID HE

§    Low to intermediate grade[236]

§    Cords and nests of epithelioid cells in myxohyaline matrix

§    Cytoplasmic vacuoles

§    Intravascular growth

§    Central hyaline necrosis

Prognosis

§    Bad

2. ANGIOSARCOMA

3. SYNOVIAL SARCOMA

Gross

§    Young adults (35), CP and SOB

§    Mostly in extremities, HN, rare on pleura

Origin

§    Epithelial (probably should be renamed as carcinoma of soft tissue)

Micro

§    Monophasic: compact fascicles of dark spindle cells with HPC-like areas, often punctuated by small arteries and capillaries in irregular distribution, monotonous look

Ø   Storiform

Ø   Herringbone

§    Biphasic with epithelial and spindle cell component

§    PD tumors have small round blue cells resembling PNET/EW

IHC: staining pattern and which cells (USCAP)

§    CK+/EMA+: focal in spindle cells

§    BCL2+

§    CD99+: both epithelial in spindle cells

§    S100+ in 30%à pitfall with melanoma and MPNST

§    VIM+

§    Calponin+

 

Prognosis

§    Aggressive

§    SYT-SSX2 better than SYT-SSX1[237]

DD

§    Sarcomatoid MM (vs monophasic SS): more pleomorphism[238], diffuse CK+, BCL2-, calponin-, no t(X;18)

§    Biphasic MM (vs biphasic SS): same as above

§    SFT

§    PNST

§    LMS

§    Melanoma

§    Carcinoma

4. SOLITARY FIBROUS TUMOUR

Clinical: large tumor? Asbestos?

§    50-60 asymptomatic usually or minor symptoms (CP, SOB)

§    Hypoglycemia, effusion, clubbing when large

§    No association with asbestos

Origin

§    Subpleural FB (USCAP)

Gross

§    Small but may be very large

§    Pedunculated polypoid from pleura (visceral> parietal)

§    Always solid white, no hemonecrosis

Does it usually cause effusion?

§    No

Micro

§    HPC BV

§    Whorls of collagen[239] with interspersed spindle cells[240]

§    Patternless pattern with hypo and hypercellular regions with alternating thick hyalinized collagen (keloid-like)

IHC

§    Bcl-2+: membranous and cytoplasmic

§    CD34+: cytoplasmic? Membranous?

§    CD99+

§    VIM+

§    CK-, EMA-, S100-, SM markers-

Prognosis: how to predict behavior?

§    Histology not reliable but some hints exist

Ø   Encapsulated, polypoid, pedunculated good

Ø   Mitoses, necrosis, atypia maybe bad[241]

Treatment: typical and atypical SFT

§    Curative if complete excision

Outcome

§    Recurrnce in 15% (just need to resect again)

SFT vs monophasic SS***

SFT	Monophasic SS
CD99+, BCL2+
CD34+	CK+[242]

SFT vs desmoplastic MM

SFT	Desmoplastic MM
CD34+	CK+

5. CALCIFYING TUMOR OF PLEURA

6. DSRCT

METS

Name 3 most common

§    Lung, breast, ovary[243][244]

 

MEDIASTINUM/THYMUS

NORMAL

§    Heart, thymus, great vessels (aorta, SVC, IVC, main pulmonary artery)

Embryology of thymus

§    With lower parathyroid, from 3^rd[245]+/-4^th pharyngeal pouches

Location of thymus

§    Neck or pleural surface

Normal thymus

§    Involutes with age but also HIV

§    Pyramid, well encapsulated, lobules by fibrous septa

§    Cortex and medulla

§    Epithelial cells (Hassall corpuscles) and immature T

BRONCHOGENIC CYST

§    Unilocular

§    Respiratory lining with all components of bronchus (cartilage, seromucinous glands, SM)

§    No communication with airways

§    Secondary infection possible[246]

ENTERIC CYST

§    Posterior mediastinum

§    Due to developmental defect

§    Paraesophageal, gastroesophageal

Micro

§    Squamous, columnar, pseudostratified columnar

§    Lined by gastric epithelium?

§    Subepithelial: smooth muscle, no cartilage

ESOPHAGEAL CYST

§    Squamous lining

§    Double layers of SM but no cartilage

LYMPHANGIOMA/CYSTIC HYGROMA

Micro: large, irregular lymphatic channels

MENINGOCELE

§    Posterior mediastinum

§    Communicate with meninges, usually through a defect in vertebral bodies

§    Contain clear/amber cerebrospinal fluid[247]

Micro: thick fibrous wall, lined by flattened arachnoid cells; variable neural tissue, calcification

PERICARDIAL CYST

§    Adherent to pericardium and diaphragm; may communicate with pericardial cavity

Micro

§    Fibrous tissue lined by bland mesothelium

CONGENITAL ANOMALIES OF THYMUS

Types

§    Hypoplasia or aplasia: DiGeorge[248] (severe cell-mediated immunodeficiency, hypoPTH)

§    Thymic cysts: squamous or columnar lining

THYMIC CYST

Micro

§    Few layers of bland squamoid cells and thymic tissue in wall

Etio

§    Developmental

Significance

§    Noneà just make sure no tumor around

THYMIC HP (misnomer)

§    In chronic inflammation or immunologic conditions such as MG, Graves, SLE, scleroderma, RA

Micro

§    Reactive lymphoid follicles with germinal centers (B)

BRANCHIAL CLEFT CYST

§    Stratified squamous epithelium with keratin debris. Minority of cases lined by respiratory epithelium

§    Lymphoid tissue+/-germinal centers

§    Infected or ruptured possible

 

THYMIC EPITHELIAL TUMORS

THYMOMA

Clinical

§    From thymic cortical or medullary epithelial cells (not thymocytes)

§    Most common primary anterior mediastinal neoplasm

Presentation***

§    Adults >40[249]

§    Cough, SOB, mass with compression (SVC syndrome)

§    Paraneoplastic syndromes

Paraneoplastic syndromes***

§    MG

§    Acquired hypoIg

§    Pure RBC aplasia

§    Graves

§    Pernicious anemia

§    Dermatomyositis-polymyositis

§    Cushing

Location

§    Anterosuperior mediastinum, neck, thyroid, pulmonary hilus

Gross

§    White mass with cystic necrosis and calcification

Micro***

§    Bland

§    Well formed Hassall’s corpuscles lacking

§    Capsule may be thick and calcified

IHC***

§    CK+, CEA+à epithelial cells

§    CD45+, CD3+à lymphocytes (mostly T)

§    CD5+, CD70+, C-KIT+ in thymic carcinoma but not in other thymomas

Treatment

§    Excision + chemoradiation

Name 2 other tumors occurring in thymus

§    Carcinoid

§    GCT

§    Lymphoma

Outcome

§    Excellent if non or minimally invasive

Prognosis (WHO)***

§    Staging (no1)

§    Histologic type (A, AB, B1-3, C)

§    Negative margin

 

A (SPINDLE CELL; MEDULLARY)

AB (MIXED)

B1 (LYMPHOCYTE-RICH; LYMPHOCYTIC; PREDOMINANTLY CORTICAL; ORGANOID)

B2 (CORTICAL)

B3 (EPITHELIAL; ATYPICAL; SQUAMOID; WD THYMIC

CARCINOMA)

MICRONODULAR

METAPLASTIC

MICROSCOPIC

SCLEROSING

LIPOFIBROADENOMA

THYMIC CARCINOMA[250]

SCC

BASALOID CARCINOMA

MEC

LYMPHOEPITHELIOMA-LIKE CARCINOMA

SARCOMATOID (CARCINOSARCOMA)

CLEAR CELL CARCINOMA

ADENOCARCINOMA

CARCINOMA WITH t(15;19)

NE TUMORS

CARCINOIDS: TYPICAL AND ATYPICAL

SMALL CELL NE

LARGE CELL NE

UNDIFFERENTIATED

COMBINED

 

GCT

Variants (WHO)

§    Seminomaà chemoradiation, no surgery

§    Non-seminomatous GCTà chemotherapy, followed by surgery

Ø   ECà resection and chemoradiation?

Ø   YST

Ø   CC

§    Teratomaà resection

§    Mixed

LYMPHOPROLIFERATIVE

B

T

HD

HISTIOCYTIC

MESENCHYMAL

THYMOLIPOMA

LIPOMA

LS

SFT

SS

VASCULAR

RMS

LM

LMS

NEURAL

 

 

HEREDITARY

CARNEY COMPLEX

§    Carney complex

Ø   “C” “M”à cardiac myxoma

Ø   “P”à 3 pigmented lesions (pigmented cutaneous lesions, bilateral black adrenals, pigmented schwannomas)

CARNEY TRIAD

§    Paraganglioma

§    Pulmonary chondroma

§    GIST: epithelioid

§    Young women

A1AT

CYSTIC FIBROSIS

Complications

§    Bronchiectasis

§    Upper respiratory infections

Ø   Pseudomonas: produces alginate[251]. Never eradicated from lung

Ø   Staph aureus

Ø   Burkholderia cepacia (20%): unique to CF, rapid deterioration of pulmonary status and death

§    Pancreatic insufficiency[252]à steatorrhea, malabsorption

§    Males infertility (>95%)[253]

§    Meconium ileus (5-10%)

§    Intussusception

Diagnosis

§    DeltaF508 by PCR[254]

§    High sweat chloride

Genetics

§    CFTR[255] mutation

SYNDROME, CILIA, IMMOTILE

§    Half have Kartagener syndrome.

§    Due to lack of dynein arms in cilia visible on EM (Osler)

 

 

REVISED WORKING FORMULATION FOR CLASSIFICATION AND GRADING 1995 (Lester)

§    Acute rejection

Ø   A0[256]

Ø   A1

Ø   A2

Ø   A3

Ø   A4

§    Airway inflammation

Ø   B0

Ø   B1

Ø   B2

Ø   B3

Ø   B4

Ø   BX

§    Chronic rejection (bronchiolitis obliterans)

Ø   Active

Ø   Inactive

LUNG STAGING & TREATMENT

§    TIS: BAC?

§    T1: <3cm sizeà lobectomy if hilar LN negative

§    T2[257]: >3cm size or visceral pleura[258] or bronchus (>2cm from carina) or lobar atelectasisà lobectomy or pneumonectomy? Does it depend more on hilar LN or T stage?

§    T3: non-organs (chest wall, diaphragm, pericardium, mediastinal pleura) or bronchus (<2cm from carina but without carina) or entire lung atelectasisà pneumonectomy with en block dissection if no distant metastasis (Lester)

§    T4: direct to organs (esophagus, mediastinum, heart, trachea, carina, vertebra, great BV) or malignant effusion or tumor of same morphology inside same lobe

§    N1[259]: ipsilateral peribronchial or hilar[260] or intrapulmonaryà pneumonectomy because hilar LN+

§    N2: ipsilateral mediastinal[261] or subcarinal[262]à surgery aborted because mediastinal LN+

§    N3: ipsilateral scalene or supraclavicular, internal mammary? or any contralateral

§    M1: nodules in different lobes of different morphology

INDICATIONS PNEUMONECTOMY

§    Fissure+

§    Any hilar tumor (T2 tumor)

§    Hilar LN+ (still intraparenchymal but sits between lobar bronchi)

§    Multilobar

INDICATIONS FOR LOBECTOMY

§    T1 tumor (positive peribronchial LN but negative hilar LN)

 

INDICATIONS FOR WEDGE RESECTION

§    Suspicious pleural nodule

§    Tumour resection if patient cannot tolerate pneumonectomy.

INDICATIONS FOR BULLECTOMY

§    Severe emphysema

GROSSING WEDGE RESECTION

WOMEN FPI SEPS D

§    Check req and unique no.

§    Check history

Special things to include

§    Measureà staple line

§    Examine

Ø   à pleural surface (smooth, retracted, tumour, lymphangiectatic spread, adhesions)

Ø   à non-neoplastic lung

GROSSING PNEUMONECTOMY

Check WOMEN FP SEPS

§    Check req and unique no.

§    Check history

Special things to include

§    Examine

Ø   Pleural surface

Ø   Non-neoplastic lung

Ø   Chest wall, mediastinum

Ø   Lymph nodes (bronchial N1, mediastinal N2)

§    Fixà inflate lung

§    Submità bronchial margin

 

REPORT LOBECTOMY/PNEUMONECTOMY

§    Site

Ø   Names of involved bronchi and segments

Ø   Multiple tumors (intrapulmonary metastases)

§    Tumor spread

§    LN

Ø   Site, number, largest size, extracapsular

§    Margin

Ø   Bronchi, peribronchial and perivascular soft tissue

Ø   Surfaces covering tumor (pleura, thoracic wall, diaphragm), adjacent structures

§    Non-neoplastic

Ø   Presence of histologic treatment effect (if prior chemoradiation therapy)

CLASSIFICATION OF LUNG TUMORS

§    Epithelial

Ø   Benign

§    Papilloma

§    Adenoma

Ø   Pre-invasive

§    Squamous:

§    Squamous dysplasia

§    CIS

§    Glandular:

§    Bronchial atypical adenomatous HP

§    Malignant

Ø   Squamous cell ca

Ø   Adenoca

Ø   -BAC

§    -non-mucinous

§    -mucinous

§    -mixed (both)

Ø   Small cell ca

Ø   Lg cell ca

Ø   Adenosquamous ca

Ø   Ca. with pleomorphic/ sarcomatoid elements

Ø   Ca with spindle cells

Ø   Carcinosarcoma

Ø   Pulmonary blastoma

Ø   Neuroendocrine type tumours

Ø   Carcinoid tumours

Ø   Typical

Ø   Atypical

Ø   Lg cell neuroendocrine ca

Ø   Non-small cell ca with neuroendocrine feat.

Ø   Tumorlet

Ø   Ca of salivary gland origin

Ø   ACC

Ø   MEC

§    Soft tissue tumours

Ø   Vascular

§    -epithelioid hemangioendothelioma

§    -sclerosing hemangioma

Ø   Clear cell (sugar) tumour

Ø   Pulmonary hamartoma

§    Mesothelial tumours

Ø   Benign

§    Adenomatoid tumour

Ø   Malignant

§    Mesothelioma

• Epithelioid mesothelioma
• Sarcomatoid mesothelioma

§    Lymphoproliferative disorders

Ø   Benign

Ø   Lymphoid interstitial pneumonia

Ø   Malignant

Ø   BALT (low grade)

Ø   Lymphomatoid granulomatosis (high grade)

§    mult. nodules

§    angio-centric/invasive/destructive

Ø   Hodgkin disease

§    TUMOUR-LIKE LESIONS

Ø   Inflammatory pseudotumour

Ø   Lymphangioleiomyomatosis

Ø   Eosinophilic granuloma

Ø   Hyalinizing granuloma

STAGING FOR MESOTHELIOMA (Lester)

§    T1: …

DIFFERENITALS FOR SPINDLE CELLS IN PLEURA***

§    Fibrous pleurisy

§    Primary sarcomas

Ø   SFT

Ø   LMS

Ø   Angiosarcoma and EHE

Ø   SS

Ø   DSRCT

Ø   EW/PNET

§    Mesothelioma

§    Mets

Ø   Melanoma

Ø   Thymic carcinoma

Ø   Sarcomatoid carcinoma

Ø   Lymphoma

WHO CLASSIFICATION, MICRO AND PROGNOSIS***[263]

§    A (spindle, medullary[264])à benign

Ø   Organotypic

Ø   Bland spindle/oval cells

Ø   Few/no thymocytes

§    AB (mixed)à benign

Ø   Mixed of lymphocyte-poor A and lymphocyte-rich Bà so, thymocyte number between A and B

§    B1 (lymphocyte-rich, lymphocytic, predominantly cortical, organoid)à LG malignancy

Ø   Small polygonal cells

Ø   Small round vesicular nuclei

Ø   No nucleoli

Ø   Abundant thymocytes

Ø   Organotypic, indistinguishable from normal thymus, cortex and medullar, +/-Hassall

§    B2 (cortical)à worse than B1

Ø   Organotypic

Ø   Large polygonal cells

Ø   Round vesicular nuclei

Ø   Nucleoli

Ø   Rich thymocytes

§    B3 (epithelial, atypical, squamoid, WD thymic carcinoma) à worse than B2, same as C if advanced

Ø   Organotypic but with cytoplogic atypia

Ø   Medium-sized round or polygonal cells

Ø   Cortical cells[265] palisading around BVà increased atypia corresponds to aggressivity

Ø   Minor medullary cells

Ø   Interspersed thymocytes

Ø   Capsule invasion (must be through-and-through)

§    Thymic carcinoma[266]***

Ø   SCC: LG

Ø   Basaloid carcinoma: LG

Ø   MEC: LG-HG depending on grade

Ø   Lymphoepithelioma-like: HBV in 50%, HG

Ø   Sarcomatoid carcinoma (carcinosarcoma): HG

Ø   Clear cell carcinoma: HG

Ø   Adenocarcinoma

Ø   Papillary adenocarcinoma

Ø   NE tumors (carcinoid, large, small cell NE): HG for small cell NE carcinoma

Ø   Undifferentiated: HG

Ø   Carcinoma with t(15:19)***: young, aggressive

THYMOMA VS THYMIC CARCINOMA

Thymoma	Thymic carcinoma
Organotypic[267]	No
No	CD5+, CD70+, C-KIT+
Variably invasive	Always
MG	No
Other AI disorders	No
Curable	Unresectable

STAGING THYMOMA

§    Extent of capsular invasion

STAGING THYMIC GCT

§    Different staging

 

 

 

 

 

 

 

 

 

 

 

 

 

 

MEDIASTINAL TUMORS BY COMPARTMENT

Superior mediastinum***

§    Terrible lymphoma

§    Thymoma

§    Thyroid

§    Parathyroid

§    Mets

Anterior mediastinum (hint: 5 T’s)[268]***

§    Terrible lymphoma

§    Thyroid

§    Thymoma

§    Teratoma (GCT)

§    Parathyroid

Middle mediastinum***

§    Bronchogenic cyst

§    Pericardial cyst

§    Lymphoma

Posterior mediastinum***

§    Neurogenic (schwannoma[269], NF)

§    Lymphoma

§    Gastroenteric hernia

Mediastinal tumors

§    Kids: lymphoma by large

§    Adults: thymoma> lymphoma> GCT

MALIGNANT SFT***

§    >4/10

§    Necrosis

§    Pleomorphic

§    >10cm

MM vs mesothelial HP

MM	Mesothelial HP
Invasion[270]: stroma, pleural plaque, fat, muscle, organ	No
No	Inflammation
No	Fibrin
No	Zonation[271]
No	Granulation tissue with ┴ capillaries
Necrosis	No
Glands or papillae or large cell groupings
Atypia, mitoses in both

Epthelioid MM vs adenocarcinoma***

Epithelioid MM	Adenocarcinoma
9 and 22 loss	Less complex
Imaging[272]***  -Encasing -Diffuse or multifocal[273] -Peripheral lung nodules[274] -Diffuse pleural thickening	Imaging  -Intraparenchymal
-More uniform cytology  -More cuboidal	-Ugly  -More nuclear crowding -More columnar
High pleural hyaluronate	High pleural CEA
Alcian blue2.5 or HCI+[275], removed by pretreatment with hyaluronidase digestion	Mucicarmine+ or PAS+[276], Alcian blue2.5 not removable with hyaluronidase pretreatment
“CCWT”  -CK5/6+[277] -Calretinin+[278] -WT1+[279] -Thrombomodulin+[280]	“TLC”  -TTF1+ -LeuM1/CD15+[281] -CEA+[282] -B72.3+[283] (HWK) -Ber-EP4+[284] (記“before”) (HMK) -BG8+ -CA19-9+ -MOC31+
-Long microvilli (10:1)[285]  -Branched -No glycocalyx coating -On all cell free surface -Abundant tonofilaments	-Short microvilli (5:1)  -Lamellar bodies -Only on apical surface -No secretory granules
-CK7+/CK20- or CK7-/CK20-  -CK+ -EMA+
Junk markers: mesothelin[286], CD99, HBME1, glycogen
Other DDx***  -Epithelioid SFT: CD34+ -Epithelioid HE: vascular markers, cytoplasmic lumens -Metastasis -Mesothelial HP

 

Sarcomatoid mesothelioma vs SFT vs SS

Sarcomatoid MM	SFT	SS
		T(X;18)***
Other DDx  -Sarcomatoid carcinoma -Fibrous pleuritis
-Use of IHC is not to confirm sarcomatoid mesothelioma but to rule other sarcomas with known phenotypes because IHC useful for sarcomatoid MM[287]  DD -LMS, MFH, SFT

Sarcomatoid MM vs fibrous pleuritis

Sarcomatoid MM	Fibrous pleuritis
Transition between cellular and acellular	No
No	Granulation tissue
No	Zonation
No	Fibrin
No	Inflammation
-Atypia, mitoses in both  -CK+ in both! -CK5/6 unreliable -Calretinin- in both -SMA+ in both[288]

Eosinophils in lungs

§    Asthma

§    Eosinophilic pneumonia

§    Churg-Strauss

§    Fungal/parasitic infections

§    Drug reactions

Cysts in lungs***

§    Infectious: Staph, Klebsiella, Echinococcus

§    LAM

§    Bronchogenic cysts, congenital cystic adenomatoid malformation,

§    Honeycomb

§    SCC with cavitation

§    COPD

§    Hemangioma

Tumors with granulomas

§    SCC with keratin

§    Seminoma

§    HD

Granulomas

§    Berylliosis

§    HS pneumonitis

§    Methotrexate

§    LIP

§    Usual

Ø   Sarcoidosis

Ø   TB

Ø   FB: talc

Ø   Bacteria: Actinomyces, Nocardia

Ø   Fungi: Aspergillus, Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Mucor, Sporotrichosis

Ø   Viruses

Ø   Syphilis

Ø   Tumors: seminoma, lymphomas,

Ø   Vasculitis: Wegener, Churg-Strauss[289], giant cell vasculitis, RA

Eosinophils

§    Acute eosinophilic pneumonia

§    Simple pulmonary hypereosinophilia (Loffler syndrome)

§    Tropical eosinophilia (microfilariae)

§    Secondary eosinophilia (parasites, fungi, bacteria, HSP, drugs, asthma, ABPA, vasculitis)

§    Chronic eosinophilic pneumonia (idiopathic)

Bronchocentric granulomatosis & angiitis “C WRAP FT”

Churg-Strauss
Wegener’s	Fungal
Rheumatoid arthritis	TB infection
Allergic bronchopulm. aspergillosis
Parasitic infections

Granulomatous interstitial inflammation “PASS DEBIT”

Pneumoconiosis (Berylliosis)	Drugs
Aspiration	Extrinsic allergic alveolitis
Sarcoidosis	Bronchocentric granulomatosis
Sjögren’s syndrome	IV talc
	Tumor

Causes of cor pulmonale

§    Pulmonary parenchyma

Ø   COPD

Ø   ILD if leads to fibrosis

Ø   pneumoconioses

Ø   CF, bronchiectasis

§    Diseases of pulmonary vessels

Ø   Primary plexogenic HTN

Ø   TE (Acute)

Ø   Mult. tumor emboli

Ø   Radiation

§    Disease of chest wall movement

Ø   Kyphoscoliosis

Ø   Neuromuscular disease

Ø   Obesity

§    Vasoconstriction

Ø   Hypoxemia

Ø   Metabolic acidosis (Acute)

Undifferentiated tumors in lung

§    Carcinoma: CKAE1/3, TTF1

§    Sarcoma: VIM

§    Lymphoma: LCA

§    Melanoma

§    NE (including Merkel): chromogranin, synaptophysin, CK20 (dot+), EMA, LMWK (?), NSE

§    GCT

§    Thymoma

§    Mesothelioma: calretinin, CD15 (LeuM1), LMK, CEA, CD5/6, CD99

Endobronchial tumors

§    Carcinoids

§    AdCC

§    MEC

IHC of small cell NE carcinoma in other sites (Archives)

§    CK20+ (paranuclear-dot)

Ø   97% in Merkel cell carcinoma

Ø   60%+ in salivary gland small cell carcinoma

§    ER+/PR+

Ø   >2/3 of breast small cell carcinoma (Archives)

§    Others outliers

Ø   Prostatic: PSA-/PAP-

Ø   Bladder: uroplakin III-, thrombomodulin-, HMW-, CD20-

Ø   Intestinal: CDX2 only 20+

Bronchiocentric fibrosis (hint: inhalation diseases)

§    HSP

§    Infection

§    Airway diseases

§    Smoking-related histiocytosis

§    RB-ILD

§    Collagen vascular disease

Necrotizing capillaritis

§    SLE

§    Wegener

§    HSP

§    Cryoglobulinemia

§    Behcet

§    Drug reactions

§    Goodpasture

SMALL ROUND BLUE CELL TUMORS

§    RMS

§    PNET

§    Lymphoma

§    Small cell NE carcinoma

§    Neuroblastoma

§    Basaloid SCC

§    Melanoma

LUNG DISEASES PREDISPOSING TO SPONTANEOUS PNEUMOTHORAX

§    Histiocytosis X

§    LAM

 

 

 

 

 

 

 

 

 

 

NE TUMORS (WHO, Lester)

	Typical	Atypical[290]	Small cell NE	Large cell NE
Mitoses	≤1/10	2-10/10	>20/10 often	>11/102
Necrosis	No	Micronecrosis	Extensive	Extensive
Nucleoli	No	-Macronucleoli  -Disorganized architecture	No	Macronucleoli
Chromatin	Fine	Fine to coarse	Fine	Fine to coarse
Atypia	Atypia	Atypia	Also can be spindly
Size	?	?	Small (<3 resting lymphocytes)	Large
N/C	?	?	High	Low
Cytoplasm	Moderate	Moderate	Scant	Moderate-abundant
Azzopardi	No	No	Common	Rare
NE stains	Strong	Strong	Weaker	?
EM	Smaller and more numerous granules		Larger and fewer	?
Nodal mets	5%[291]	70%	?
Survival	90% 10-year survival	35% 10-year survival	?

CYSTS IN MEDIASTINUM

§    Foregut cysts (bronchogenic, enteric, esophageal)

§    Lung cystic lesions: lung abscess, CCAM

§    Branchial cleft cystà not sure if occur here

§    Lymphangioma

§    Meningocele

§    Parathyroid cyst

§    Pericardial cyst

§    Cystic GCT

§    Thymic cyst

§    Cystic neoplasms: thymoma, lymphoma

 

Parathyroid	Thymic	Broncho	Pericard	Enteric	Hygroma	Teratoma	Thymoma	Seminoma
Anterosup	Anterosup	Middle	Middle	Posterior	Anterosup	Anterosup	Anterosup	Anterosup
Serous	Serous or turbid	Viscous	Serous	Mucoid	Serous	Cheesy	Variable	Variable
	Cholesterol granuloma	Cartilage		SM		+/-cartilage
Cuboidal	Squamous, cuboidal, columnar or mixed	Columnar	Flat or cuboidal	Columnar	None	Variable	Polygonal or spindle	Polygonal
Unilocular	Either	Either	Unilocular	Unilocular	Multlocular	Multilocular	Either	Either