logy lecture chapter 1 - pathology of the respiratory tract 2010-2011

Pathology of the respiratory tract. 3rd year, 2010-2011

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PATHOLOGY OF THE RESPIRATORY TRACT

NOSE AND PARANASAL SINUSESINFLAMMATIONS

RhinitisAcute rhinitisInfectious:

- Viral: initial event (Ly, Pl)- Bacterial: superinfection (PMN)

Allergic: Eo (Immediate or type I hypersensitivity)Chronic rhinitis: a sequel to repeated attacks of acute rhinitis

Nasal polypsDefinition: pseudotumors of the nasal mucosa (they may be also of sinusal origin and protrude into nasal

cavities)Pathogenesis: Recurrent rhinitis – rarely allergic Associations:

Cystic fibrosis (! polyps in children under 10 years of age may be suggestive for cystic fibrosis) Kartagener syndrome

PathologyMacroscopy: Focally thickened mucosa 3-4 cm diameterMicroscopy: Covered by a normal squamous or respiratory-type epithelium ± ulcerations Stroma: edema, inflammatory cells (PMN, Eo, Ly, Pl) Glands: hyperplastic/cystically dilatedImportance: obstruction Particular forms- Antrochoanal polyp: orriginates in the maxillary sinus mucosa and may protrude through the choanal orifice

- Macroscopy: it has a cystic intramaxillary portion and a solid intranasal portion.- Polyps in patients with cystic fibrosis (CF):

- 20% of patients with CF- May precede with 12 years the clinical features of CF- In children with nasal polyps CF must be excluded!!!- Microscopy: cystically dilated glands, filled with viscous mucus

SINUSITISDefinition: inflammation of the mucosa of paranasal sinusesAcute sinusitisPathogenesis:- Most commonly preceded by acute or chronic rhinitis- Maxillary may arise by extension of a periapical infectionEtiology:- Bacteria: usually the microbial flora of the oral cavityChronic sinusitisPathogenesis:- Repeated attacks of acute sinusitis- Kartagener syndrome: rare; chronic sinusitis + bronchiectasis + situs inversusEtiology:- Bacteria- Fungi: severe cases, in diabetics (mucormycosis) particularly when there is interference with drainage.


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Complications of sinusitis: Obstruction – it will result in:

Mucocele: retention of mucous secretions in a closed sinusal cavity Empyema: the sinusal cavity is filed with pus

Cavernous sinus thrombophlebitis: may be fatal Osteomyelitis Cellulitis/orbital abscess Intracranial infections: meningitis, brain abscess

TUMORS OF THE NOSE AND PARANASAL SINUSESBenign tumors

Papilloma of the noseDefinition: benign tumor of the sinonasal mucosaEtiology: HPV 6,11Clinical features: M, 50 years, obstruction, epistaxisPathologyMacroscopy: Exophytic papilloma:

On the nasal septum Fungating tumoral mass, friable → bleeds easily

Endophytic (inverted): On the lateral walls of the nose Extends into the mucosa

Microscopy: basaloid cells with areas of squamous differentiationEvolution: inverted papilloma:

May reccur May extent to the orbit o the cranial vault Malignization: rarely

Malignant tumorsCarcinoma of the nasal cavities and of the paranasal sinusesSites: > 50 - antrum of the maxillary sinus 1/3 – nasal cavity 10 - ethmoid sinusFavoring factors: HPV, Cr, Ni, hydrocarburesClinical features: Nasal obstruction, rhinorrhea, epistaxis Pain and paresthesias of the face Headache Visual disturbancesPathologyMacroscopy: Vegetant UlcerativeMicroscopy: Squamous cell carcinoma Adenocarcinoma, adenosquamos carcinoma Transitional cell carcinomaEvolution: discovered in advanced stages → poor prognosis


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Olfactive neuroblastoma (esthesioneuroblastoma)Definition: malignant neuroectodermal tumor thought to arise from the neuroendocrine cells of the olfactorymucosaEpidemiology:- Rare- Median age 50 years, range 3-79 years- M=FLocation: usually upper nasal vault; rarely in nasopharynx, maxillary or ethmoid sinusPathologyMacroscopy: polypoid mass, red-gray, highly vascular, soft consistencyMicroscopy:- Nests or sheets of uniform small cells with scant cytoplasm and round nuclei- Prominent fibrillary background- Very vascular- Necrosis (it represents a poor prognostic factor)- Immunohistochemistry: cells are positive for neuroendocrine markers: neuron specific enolase (NSE)- Electron microscopy: dense core neurosecretory granulesClinical features: nasal obstruction, epistaxis, exophtalmos, facial asymmetryEvolution: locally invasive into paranasal sinuses, nasopharynx, palate, orbit, base of skull, brainMetastases: cervical lymph nodes, at distant sitesTreatment: combined (surgery, RT, CHT)

PATHOLOGY OF THE NASOPHARYNXInflammations: pharyngitis, tonsillitis

Etiology:- Viruses: rhino, adeno, echo, respiratory sincitial, flu- Bacteria: streptoccocus, staphylococcus, diphteric bacillusFormes of disease:- Acute tonsillitis- Follicular tonsillitis: reactive hyperplasia of the lymphoid structures; crypts are filled with exudate- Pseudomembranous tonsillitis: diphteria, Plaut-Vincent angina (fusospirils)- Reccurent or chronic tonsillitisComplications:- Post-streptococcal: glomerulonephritis, rheumatic fever- Peritonsillar abscess - may extent to the following structures:

- Airways- Parapharyngeal space → erosion of the carotid artery → fatal hemorrhage- Mediastinum → fatal suppurative mediastinitis- Base of the brain→ purulent meningitis

TUMORS OF THE NASOPHARYNXBenign tumors

Nasopharingeal angiofibroma- Adolescents males (10-25 years), rarely in older patients or women (may be misdiagnoses)- 75% have androgen receptors, but not estrogen or progesterone receptorsOrigin: arises from erectile-like fibrovascular stroma in the posterolateral wall of the roof of the nosePathologyMacroscopy:- Well circumscribed but unencapsulated polypoid fibrous mass- Bleeds severely on manipulation and biopsy- May occlude nares- Spongy cut surface


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Microscopy:- Blood vessels with imperfect muscular wall- Fibrous stroma with variable cellularityEvolution:- May grow into nasopharynx, orbit or cranial cavity- May regress after puberty, especially after incomplete surgical excision or radiation therapy- Benign but recurs in 40%, usually within 1 year, particularly if not completely removed- Rare sarcomatous transformation after radiation therapyTreatment:- Surgery (difficult to excise)- Preoperative embolization or anti-androgen therapy- Chemotherapy or radiation therapy if advanced or aggressive

Malignant tumorsNasopharyngeal carcinomaEpidemiology:- The most common cancer of the nasopharynx- High incidence: EBV- Africa: the most common cancer in children- China: adults- M>F- Age: bimodal distribution - 15-25 years and 60-69 yearsFavoring factors: heredity, EBV infection, environmentPathologyMicroscopy:- Keratinizing squamous cell carcinoma: elderly, no EBV infection- Nonkeratinizing squamous cell carcinoma

DifferentiatedUndifferentiated (“lymphoepithelioma”): tumor cells are intermixed with lymphocytes

Clinical features, evolution:- Most commonly begins as an unilateral cervical lymphadenopathy- Growths slowly → diplopia, otitis media, hearing disturbances- Extension to the paranasopharyngeal space → growths along the trigeminal nerve- At the moment of the diagnosis: unresectable, with local (lymph nodes) and distant metastases (bones)Treatment: radiotherapy (RT) + surgeryPrognosis: 60% 5-year survival (with treatment)

PATHOLOGY OF THE LARYNX

REACTIVE NODULES (PSEUDOTUMORS): VOCAL CORD NODULES AND POLYPSDefinition: noninflammatory response to injury causing hoarsenessSynonym: laryngeal nodule, singer’s noduleFavoring factors:- More common in heavy smokers or individuals who impose great strain on their vocal cords (singers'nodules)Pathology- Located on the true vocal cords- By convention, unilateral lesions are named vocal polyps, and bilateral lesions are named vocal nodulesMacroscopy:- Smooth, round, 1-3 mm growths on the anterior third of the vocal cord- Larger nodules and bilateral nodules may present ulcerations


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Microscopy:- Covered by a stratified squamous epithelium- Stroma is usually edematous- Microscopic variants:

- Telangiectatic: polyps with numerous thin-walled dilated vessels- Gelatinous: myxoid stroma with fibroblasts and thin walled vessels

Evolution:- Almost never transforms to malignancy- May reccurClinical features:- Change the character of the voice- Often cause progressive hoarsenessTreatment: excision or vocal rest

TUMORSBenign tumors

PapillomaGeneralities- True vocal cords- Single/multipleMultiple papillomas- Children, adolescents (juvenile laryngeal papillomatosis)- HPV-6, 11- Microscopy: koilocytosis- Clinical features: hoarseness, dysphonia- Evolution: recurrences; radiotherapy may transform papillomatosis in carcinomaSolitary papilloma- Adults, males- Malignization: rare

Malignant tumors: Laryngeal carcinomaRisk factors: smoking, alcohol abuse, HPV (16, 18)Epidemiology: M:F=7:1, older adults, elderlyPathologyLocation: glottic (65%), supraglottic, subglottic, transglotticMacroscopy:- Plaque: gray, pearled, wrinkled- Exophytic- UlcerativeMicroscopy:- Squamous cell carcinoma: more than 95%

- Variants:- Veruccous carcinoma: very well differentiated, minimally invasive, may reach 10 cm!- Spindle cell carcinoma (sarcomatoid carcinoma): very aggressive

- Histogenesis: leukoplakia, keratosis (dysplasia, carcinoma in situ)- Adenocarcinoma- Neuroendocrine carcinomaClinical features: hoarseness, coughing, hemoptysisEvolution:- Local extension- Lymph nodes metastases: cervical region- Distant hematogenous metastases: rarely, in later stagesPrognosis: 5-year survival > 60% with surgery and RT


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PULMONARY HYPERTENSIONDefinition: increase of the mean pulmonary pressure to reach one fourth of systemic levels

Clinical classification of the pulmonary hypertension (WHO, 2003)1. Pulmonary arterial hypertension (PAH)2. Pulmonary hypertension with left heart disease3. Pulmonary hypertension associated with lung diseases and/or hypoxemia4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease5. Miscellaneous

Common etiologies: Structural cardiopulmonary conditions that increase pulmonary blood flow and/or pressure Pulmonary vascular resistance Left heart resistance to blood flowExamples: Chronic obstructive or interstitial lung diseases Antecedent congenital or acquired heart disease: mitral stenosis Recurrent thromboembolism Connective tissue diseases: systemic sclerosis Obstructive sleep apneaPathologyThe most common findings:- Medial hypertrophy of muscular and elastic arteries- Atheromas of pulmonary artery and its major branches- Right ventricular hypertrophy- Lung biopsy is necessary to evaluate the grade of the lesions and to decide the therapy!!!Microscopic findings:- Lesions can involve the entire arterial tree, from the main pulmonary arteries to the arterioles Pulmonary artery and its main branches: atherosclerosis (in severe cases) Arterioles and small arteries (of 40-300 µm diameter):

The most commonly affected Changes are more severe in idiopathic arterial pulmonary hypertension Lumen is occluded or very narrowed (“pinpoint channels”) Lesions:

Medial hypertrophy and arteriolar muscularization Intimal cell proliferation Lamellar concentrically intimal fibrosis (“onionskin”) Dilative lesions (angiomatoid lesions) Plexiform lesions (plexogenic pulmonary arteriopathy): a tuft of capillary formations that spans

the lumens of dilated thin-walled small arteries and may extend outside the vessel Fibrinoid necrosis of the wall (necrotizing angiitis)

Clinical course- Idiopathic PH: most common in women of 20 to 40 years of age and, occasionally, in young children- Clinical signs and symptoms of all forms of hypertension become evident only with advanced disease:

- Dyspnea and fatigue- Angina-type chest pain- Severe respiratory distress, cyanosis, and right ventricular hypertrophy- Death: within 2 to 5 years in 80% of patients

Treatment- Conventional therapies (oxygen, calcium channel blockers, anticoagulation, digoxin, and diuretics)- Prostacyclin analogues, endothelial receptor antagonists, inhaled nitric oxide, etc.- Lung transplantation provides definitive treatment for selected patients- Gene therapy may be possible for humans in the future


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ATELECTASISDefinition: incomplete expansion of the lungs (neonatal atelectasis) or to the collapse of previously inflatedlung, producing areas of relatively airless pulmonary parenchymaClassification of atelectasis Obstruction (resorption) atelectasis Compression atelectasis Patchy atelectasis (microatelectasis) Contraction atelectasis (the only irreversible form)

- Obstruction (resorption) atelectasisEtiopathogenesis: complete obstruction of an airway which, in time, leads to resorption of the air trapped inthe dependent alveoliCauses:- Excessive secretions within smaller bronchi: bronchial asthma, chronic bronchitis, bronchiectasis,

postoperative states- Aspiration of foreign bodies- Bronchial tumorsEffects:- Involves parts of the lung- Lung volume is diminished- The mediastinum shifts toward the atelectatic lung

- Compression atelectasisEtiopathogenesis: compression of the parenchyma will evacuate the air from the alveolar spacesCauses:- Pleural effusions: exudate, transudate (cardiac failure), blood, air (pneumothorax)- Pleural tumors- Abnormal elevation of the diaphragm: peritonitis, ascitis, abdominal tumor, subdiaphragmatic abscessEffects:- Involves the entire lung (usually)- Air is eliminated from the alveoli- Mediastinum shifts away from the affected lung

- Patchy atelectasis (Microatelectasis)Etiopathogenesis: loss of pulmonary surfactant- Occurs in neonatal or adult respiratory distress syndrome

- Contraction atelectasisEtiopathogenesis: local or generalized fibrotic changes in pleura or lung preventing full expansion of the lung

Pathology of atelectasisMacroscopy: If a small volume of lung is collapsed, the pleura is dark and shrunken below the level of the pink, well-

expanded lung. When an entire lobe or lung is affected, the pleura is wrinkled The involved parenchyma is dark-red, contracted (depressed if focal atelectasis is present), firm, and

without crepitanceMicroscopy: The alveolar walls are compressed, giving the tissue a solid appearance Alveolar spaces are narrowed, lined by cuboidal pneumocytes The blood vessels of the alveolar walls are large, filled with blood (explains the red color in macroscopy)Evolution:- Reversible: lung parenchyma can be re-expanded (except contraction atelectasis)- Significant atelectasis reduce oxygenation and predispose to infection- If causes are not removed, the atelectatic parenchyma of the lung will suffer fibrosis (irreversible)


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CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)Definition: group of diseases that share one major symptom - dyspnea - and are accompanied by chronic orrecurrent obstruction to airflow within the lungIncidence: Increasing (cigarette smoking, environmental pollutants) Major cause of activity- restricting or bed-confining disability in developed statesForms of disease: Emphysema Chronic bronchitis Bronchiectasis Asthma

1. EmphysemaDefinition: a condition of the lung characterized by irreversible enlargement of the airspaces distal to theterminal bronchiole, accompanied by destruction of their walls without obvious fibrosisIncidence: is present in approximately 50% of cases of autopsy in adultsPathogenesis:

Protease – antiprotease hypothesis: alveolar wall destruction and airspace enlargement after excess protease orelastase activity unopposed by appropriate antiprotease regulation Emphysema is seen to result from the destructive effect of high protease activity in subjects with low antiprotease

activity α1-antitrypsin:

Normally present in serum, tissue fluids and macrophages Major inhibitor of proteases secreted by neutrophils during inflammation Encoded by codominantly expressed genes on the proteinase inhibitor (Pi) locus on chromosome 14 Normal phenotype: Pi MM α 1-antitrypsin deficiency: Pi ZZ

Any stimulus that increase neutrophil or macrophages in the lung with release of protease leads to elastic tissuedamage

The protease-antiprotease hypothesis explains the effect of cigarette smoking in the production of centriacinaremphysema:

Smoking: Favors accumulation of neutrophils within the alveoli Stimulates release of elastase Enhances elastase activity in macrophages (macrophage elastase is not inhibited by α1-antitrypsin) Contains reactive oxygen species (free radicals) → tissue damage

Imbalance of oxidants and antioxidants hypothesis:- The normal lung contains antioxidants (superoxide dismutase, glutathione) that keep oxidative damage to a minimum- Tobacco smoke and activated neutrophils are responsible for increased amounts of reactive oxygen species (free

radicals) in the alveoli- The oxidative injury also inactivates the native antiproteases, resulting in “functional” α1-antitrypsin deficiency even

in patients without enzyme deficiency.

Classification of emphysema Centriacinar (centrilobular) emphysema Panacinar (panlobular) emphysema Distal acinar (paraseptal) emphysema Airspace enlargement with fibrosis (irregular emphysema)


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Centriacinar (centrilobular) emphysema- Involves the central or proximal parts of the acini (respiratory bronchioles)- Distal alveoli are spared- Both emphysematous and normal airspaces exist within the same acinus and lobule- More common and usually more severe in the upper lobes, particularly in the apical segments- The walls of the emphysematous spaces often contain large amounts of black pigment- Inflammation around bronchi and bronchioles is common- Occurs predominantly in heavy smokers, often in association with chronic bronchitis

Panacinar (panlobular) emphysema- The acini are uniformly enlarged from the level of the respiratory bronchiole to the terminal blind alveoli- Not to the entire lung- Tends to occur more commonly in the lower zones and in the anterior margins of the lung- Usually most severe at the bases- Associated with α1-antitrypsin (α1-AT) deficiency

Distal acinar (paraseptal) emphysema- The distal part of the acinus is predominantly involved (the proximal portion is normal)- Is more striking adjacent to the pleura, along the lobular connective tissue septa, and at the margins of the

lobules- Occurs adjacent to areas of fibrosis, scarring, or atelectasis- Usually more severe in the upper half of the lungs- The characteristic findings: multiple, continuous, enlarged airspaces from less than 0.5 cm to more than 2.0

cm in diameter, sometimes forming cyst-like structures- Probably underlies many of the cases of spontaneous pneumothorax in young adults

Airspace Enlargement with Fibrosis (Irregular Emphysema)- The acinus is irregularly involved- Almost invariably associated with scarring- The most common form of emphysema- In most instances asymptomatic and clinically insignificant

Pathology of emphysema:Macroscopy:- Advanced emphysema: lungs are enlarged, overlapping and hiding the heart- Hyperinflated, pale- The upper two thirds of the lungs are more severely affected- Irregular emphysema secondary to scarring and distal acinar emphysema: large apical blebs or bullae- Large alveoli can easily be seen on the cut surface of formalin-inflated fixed lung


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Microscopy- Abnormally large alveoli separated by thin septa- Loss of attachments of the alveoli to the outer wall of small airways- Alveolar walls are destroyed → there is decrease in the capillary bed (explains why lungs are pale)- With advanced disease, even larger abnormal airspaces may occur: blebs or bullae, which often deform

and compress the respiratory bronchioles and vasculature of the lung- Inflammatory changes may be seen in small airways

Effects on pulmonary function Loss of the lung elastic recoil → decreased expiratory airflow Respiratory bronchioles collapse during expiration (due to reduced elastic fibers in the lung) Decrease of the surface for gas changes due to the loss of the alveolar wallsClinical features Progressive dyspnea with prolonged expiration, no cyanosis („pink puffers”) Cough and expectoration (if associate bronchitis is present) Weight loss Barrel-chested Secondary pulmonary hypertension cor pulmonale congestive heart failureRx: lungs are hyperinflated: large, hide the heart

Particular forms of emphysemaCompensatory hyperinflation (emphysema) Dilation of alveoli but not destruction of septal walls in response to loss of lung substance elsewhere Example: the hyperexpansion of the residual lung parenchyma that follows pneumectomy or lobectomyObstructive overinflation The lung expands because air is trapped within it Examples:

After subtotal obstruction by a tumor or foreign object: A ball-valve action of the obstructive agent (air enters on inspiration but cannot leave onexpiration) Ventilation through collaterals

Congenital lobar overinflation in infants Obstructive overinflation can be a life-threatening emergency, because the affected portion distends

sufficiently to compress the remaining normal lung.Bullous emphysema Large subpleural blebs or bullae (spaces more than 1 cm in diameter in the distended state) that can occur in

any form of emphysema They represent localized accentuations of emphysema Occur near the apex, sometimes in relation to old tuberculous scarring On occasion, rupture of the bullae may give rise to pneumothorax.Interstitial emphysema The entrance of air into the connective tissue stroma of the lung, mediastinum, or subcutaneous tissue Alveolar tears in pulmonary emphysema provide the avenue of entrance of air into the stroma of the lung:

coughing plus some bronchiolar obstruction (whooping cough, obstruction to the airways, artificialventilation)

A wound of the chest that allows air to be sucked in or a fractured rib that punctures the lung substance


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2. Chronic bronchitisDefinition: persistent cough with sputum production for at least 3 months in at least 2 consecutive years, in

the absence of any other identifiable cause.Pathogenesis: The primary or initiating factor: long-standing irritation (tobacco smoke -90% of patients are smokers, dust from

grain, cotton, and silica)- The earliest feature of chronic bronchitis: hypersecretion of mucus in the large airways, associated with

hypertrophy of the submucosal glands in the trachea and bronchi- Subsequently: marked increase in goblet cells of small airways → excessive mucus production that

contributes to airway obstruction- The role of infection: in maintaining chronic bronchitis and in producing acute exacerbations.

PathologyMacroscopy:- Lumen of bronchi and bronchioles: filled with mucous, mucopurulent or purulent secretions Bronchial mucosa: hyperemia, edemaMicroscopy:- Chronic inflammation of the airways: lymphocytes, plasma cells- Mucous gland hyperplasia:

- Enlargement of the mucus-secreting glands of the trachea and bronchi- Increased Reid index (> 0.4): the ratio of the thickness of the mucous gland layer to the thickness

of the wall between the epithelium and the cartilage (normal value: 0.4)- Increased number of goblet cells- The bronchial epithelium: squamous metaplasia and dysplasia- Narrowing of bronchioles: mucus plugging, inflammation, and fibrosis- Bronchiolitis obliterans:

- Obliteration of lumen due to fibrosis- In the most severe cases

Clinical features- Persistent productive cough- With time: hypercapnia, hypoxemia, and mild cyanosis (“blue bloaters”)- Longstanding severe chronic bronchitis commonly leads to cor pulmonale with cardiac failure- Death may also result from further impairment of respiratory function due to superimposed acute infections

3. BronchiectasisDefinition: permanent dilation of bronchi and bronchioles caused by destruction of the muscle and elastictissue, resulting from or associated with chronic necrotizing infectionsFavoring factors: Postinfectious conditions Bronchial obstruction Other conditions, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and

post-transplantation (chronic lung rejection, and chronic graft-versus-host disease after bone marrow transplantation)Classification: Obstructive bronchiectasis

Obstruction (due to tumor, foreign body, inspissated mucus) causes resorption of air distal to obstruction,atelectasis, intraluminal secretions, destruction of the bronchial wall, dilation

Nonobstructive bronchiectasis (inflammatory) Thought to result from repeated pneumonia: increased negative intrapleural pressure due to pneumonitis and

atelectasis, transmitted through solid nonexpansible pulmonary tissue to elastic and expansible bronchialwalls, which dilate as result. Usually left sided, affecting lower lobes.

Etiology:- Necrotizing pneumonia (staphylococcus, tuberculosis)- Allergic bronchopulmonary aspergillosis- Cystic fibrosis: obstruction due to mucus plugs; infection is due to decreased ciliary clearance of bacteria- Kartegeners syndrome


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PathologyMacroscopy

- Usually within the lower lobes bilaterally, particularly involves bronchi that are vertical- Most severe in the more distal bronchi and bronchioles- The airways are dilated: up to four times normal size- The dilated bronchi and bronchioles can be followed almost to the pleural surfaces (normally they interrupt

at 2-3 cm under the pleura)- On the cut surface bronchiectasis appears as cysts filled with mucopurulent secretions- Shape of bronchial dilatation: saccular, cystic, cylindric- Bronchial walls irregularly thickened- Intervening lung parenchyma: variable inflammation and fibrosis- Peribronchial abscessesMicroscopy

- The histologic findings vary with the activity and chronicity of the disease:- In chronic cases: lymphocytes- In acute (active) cases: neutrophils within the walls

- Desquamation of the lining epithelium- Extensive areas of ulceration- Squamous metaplasia of the remaining epithelium- Lung abscesses- Fibrosis: bronchial and bronchiolar walls, peribronchiolar

Clinical features:- Cough- Fever- Copious amounts of foul-smelling, purulent sputumComplications Acute episodes Colonization with Aspergillus fumigatus aspergilloma Metastatic abscesses (brain) Pulmonary hypertension, cor pulmonale Amyloidosis

4. AsthmaDefinition: Chronic relapsing inflammatory disorder characterized by hyperreactive airways, causingepisodic, reversible bronchoconstrictionThe hallmarks of the disease are:- Increased airway responsiveness to a variety of stimuli, resulting in episodic bronchoconstriction- Inflammation of the bronchial walls- Increased mucus secretionStatus asthmaticus: unremitting attacks due to exposure to previously sensitized antigen; may be fatalClassification:- Extrinsic: type I hypersensitivity (atopic, occupational, allergic bronchopulmonary aspergillosis)- Intrinsic: nonimmune (aspirin ingestion, pneumonia, cold, stress, exercise)PathologyMacroscopy:- Status asthmaticus:

- The lungs are overdistended because of overinflation, with small areas of atelectasis- The most striking macroscopic finding: occlusion of bronchi and bronchioles by thick mucus plugs

Microscopy:- Within the lumen:

- Curschmann spirals: spiral shaped mucus plugs- Whorls of shed epithelium- Numerous eosinophils and Charcot-Leyden crystals (collections of crystalloid made up of an

eosinophil membrane protein)


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- “Airway remodeling”:- Overall thickening of airway wall- Thickened basement membrane- Increased vascularity- An increase in size of the submucosal glands and mucous metaplasia of airway epithelial cells- Hypertrophy and/or hyperplasia of the bronchial wall muscle

CHRONIC DIFFUSE INTERSTITIAL (RESTRICTIVE) DISEASESDefinition: heterogeneous group of disorders characterized predominantly by inflammation and fibrosis of thepulmonary connective tissue, principally the most peripheral and delicate interstitium in the alveolar wallsIncidence: 15% of noninfectious lung diseasesEtiopathogenesis: most commonly unknownClinical features, Rx, physiopathology: similar traits, restrictive diseasesChest radiographs: bilateral infiltrative lesions in the form of small nodules, irregular lines, or ground-glassshadowsEvolution: pulmonary hypertension, right-sided heart failure, cor pulmonalePathology- The entities can often be distinguished in the early stages- The advanced forms are hard to differentiate- Effects: scarring and gross destruction of the lung → end-stage lung or honeycomb lungClassification:- Fibrosing diseases- Granulomatous diseases- Eosinophilic pneumonia- Smoking – related diseases- Other

1. Fibrosing diseasesIdiopathic pulmonary fibrosis (Usual interstitial pneumonia- UIP, Idiopathic pulmonary

fibrosis/cryptogenic fibrosing alveolitis)Definition: clinicopathologic syndrome with characteristic radiologic, pathologic, and clinical featuresPathogenesis: “Repeated cycles” of epithelial activation/injury by some unidentified agent Abnormal epithelial repair gives rise to exuberant fibroblastic/myofibroblastic proliferation, leading to the

“fibroblastic foci” that are characteristic of IPF There is inflammation (TH2 type T cells), but the significance of the inflammatory response is unknown TGF-β1 is the driver the aberrant epithelial repair

- Is released from injured type I alveolar epithelial cells- Is fibrogenic- It favors the transformation of fibroblasts into myofibroblasts and deposition of collagen and other

extracellular matrix molecules

PathologyMacroscopy: The pleural surfaces of the lung are cobblestoned (retraction of scars along the interlobular septa) The cut surface shows fibrosis (firm, rubbery white areas) of the lung parenchyma:

Lower-lobe In the subpleural regions Along the interlobular septa

Microscopy: The hallmark of UIP is patchy interstitial fibrosis, which varies in intensity and age The earliest lesions contain exuberant fibroblastic proliferation (fibroblastic foci) With time these areas become more collagenous and less cellular


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The dense fibrosis causes the destruction of alveolar architecture and formation of cystic spaces lined byhyperplastic type II pneumocytes or bronchiolar epithelium (honeycomb fibrosis)

Typical: is the coexistence of both early and late lesions: areas of dense collagenous fibrosis withrelatively normal lung and fibroblastic foci

Inflammation: mild to moderate (Ly and few Pl, PMN, Eo, mast cells) within the fibrotic areas Foci of squamous metaplasia and smooth muscle hyperplasia may be present Pulmonary arterial hypertensive changes: intimal fibrosis and medial thickening In acute exacerbations: diffuse alveolar damage is superimposed on the UIP pattern

Clinical course: IPF begins insidiously: gradually increasing dyspnea on exertion, dry cough Most patients are 40 to 70 years old at the time of presentation Hypoxemia, cyanosis, and clubbing occur late in the course The progression: unpredictable

Gradual deterioration of the pulmonary status, despite medical treatment Acute exacerbations of the underlying disease with a rapid downhill clinical course

The mean survival is 3 years or less Risk for pulmonary adenocarcinomaTreatment:- Steroids, cyclophosphamide, or azathioprine)- Lung transplantation is the only definitive therapy currently available

PneumoconiosesDefinition: non-neoplastic lung reactions to inhalation of mineral dusts encountered in the workplaceNow it also includes diseases induced by organic as well as inorganic particulates and chemical fumes andvapors

Pathogenesis- The development of pneumoconiosis depends on:

- The amount of dust retained in the lung and airways- The size, shape, and buoyancy of the particles - the most dangerous particles range from 1 to 5 μm in

diameter because they may reach the terminal small airways and air sacs and settle in their linings.- The particle solubility and physiochemical reactivity

- Additional effects of other irritants (e.g., concomitant tobacco smoking).- Genetic factors?

a. Coal workers' pneumoconiosis (CWP, Antrachosis)Forms of the disease:1) Asymptomatic anthracosis2) Simple CWP with little to no pulmonary dysfunction3) Complicated CWP, or progressive massive fibrosis (PMF)Pathogenesis:- Anthracosis is the most innocuous coal-induced pulmonary lesion in coal miners- Is also seen in urban dwellers and tobacco smokers- Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the connective

tissue along the lymphatics, including the pleural lymphatics, or in organized lymphoid tissue along the bronchi or inthe lung hilus.

PathologySimple CWP- Coal macules (1 to 2 mm in diameter): consists of carbon-laden macrophages- Coal nodules: contain small amounts of a delicate network of collagen fibers

- They are located primarily adjacent to respiratory bronchioles, the site of initial dust accumulationThe upper lobes and upper zones of the lower lobes are more heavily involved- Dilation of adjacent alveoli may occur: centrilobular emphysema


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Complicated CWP (progressive massive fibrosis)- Occurs on a background of simple CWP- Generally requires many years to develop- Intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter:

- Usually multiple- Microscopically: dense collagen and pigment; the center of the lesion is often necrotic, most likely

due to local ischemiaClinical course- Usually a benign disease- Lung function is normal- Rarely increasing pulmonary dysfunction, pulmonary hypertension, and cor pulmonale- Association: rheumatoid arthritis → Caplan syndrome

b. SilicosisDefinition: lung disease caused by inhalation of crystalline silicon dioxide (silica)- Usually after decades of exposure- Slowly progressing, nodular, fibrosing pneumoconiosisOccupations with high risk for silicosis:- Sandblasters- Hard rock mine workers- Foundry work- Stone cutting Pathogenesis- Crystalline forms of siliccs are more fibrogenic - quartz is most commonly implicated- After inhalation, the particles interact with epithelial cells and macrophages- Within the macrophages silica causes activation and release of fibrogenic mediators

PathologyMacroscopy- In early stages: tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the

upper zones of the lungs- With time:

- Nodules may coalesce into hard, collagenous scars- Some nodules may undergo central softening and cavitation (superimposed tuberculosis or

ischemia)- Fibrotic lesions in the hilar lymph nodes and pleura- Thin sheets of calcification occur in the lymph nodes: eggshell calcification on Xrays- In advanced stages: expansion and coalescence of lesions may produce progressive massive fibrosis

Microscopy:- Nodules:

- Concentric layers of hyalinized collagen surrounded by a dense capsule of more condensed collagen- Examination of the nodules by polarized microscopy reveals the birefringent silica particles

Clinical course- Shortness of breath in late stages: progressive massive fibrosis- The disease may be progressive even if the patient is no longer exposed- Increased susceptibility to tuberculosis (depression of cell-mediated immunity)- Carcinogenic


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c. Asbestos-related diseasesAsbestos: family of crystalline hydrated silicates that form fibersUse of asbestos is seriously restricted in many developed countriesDiseases associated with asbestos exposure:- Localized fibrous plaques or, rarely, diffuse pleural fibrosis- Pleural effusions- Parenchymal interstitial fibrosis (asbestosis)- Lung carcinoma- Mesotheliomas- Laryngeal and perhaps other extrapulmonary neoplasms, including colon carcinomas

2. Granulomatous diseases

SarcoidosisDefinition: multiorgan disease of unknown etiology which frequently affects the lung, and commonlyinvolves the lymph nodes, liver, spleen, skin, heart, eye, and other organsDefinitive diagnosis: clinical features + radiologic findings + histologic evidence of noncaseatinggranulomatous inflammation (granulomas of known cause and local sarcoid reactions must be excluded)The most common clinical pattern: bilateral hilar lymphadenopathy or lung involvement is visible on chest radiographsin 90% of casesEpidemiology: F>M, 20-40 years USA:

Incidence is 10 times higher in American blacks (HLA-DR 11, 12, 14, 15, and 17) than in whites Rare among Chinese and Southeast Asians

International: Sweden↑Etiopathogenesis:Etiology: is unknownMechanism: disordered immune regulation in genetically predisposed individuals exposed to certain environmentalagents

PathologyNoncaseating granulomas in all involved tissues:

- Epithelioid cells- Langhans or foreign body–type giant cells - may have cytoplasmic inclusions:

- Schaumann bodies: laminated concretions composed of calcium and proteins- Asteroid bodies: stellate inclusions

Chronic granulomas:- Enclosed within fibrous rims or- May be replaced by hyaline fibrous scars- Usually NO necrosis (differential diagnosis with tuberculosis)

The lungs:Macroscopy: noncaseating, noncavitated nodular consolidations, of 1-2 cm diameter (in advanced cases,

formed by coalescent granulomas)Microscopy:

- Granulomas:- Along the lymphatics, around bronchi and blood vessels, in the alveolar walls- In the bronchial submucosa: seen on bronchoscopic biopsies!!!

- Varying stages of fibrosis and hyalinization are often found (healing of granulomas)

Other organs that are involved: lymph nodes, tonsils, spleen, liver, bone marrow, skin (erythema nodosum –not pathognomonic), eye (iritis or iridocyclitis → corneal opacities, glaucoma, and total loss of vision),lacrimal glands → suppression of lacrimation, salivary glands, heart, kidneys, central nervous system,endocrine glands


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Mikulicz syndrome: bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands (may be alsoproduced by other disorders)Clinical course

- May be discovered unexpectedly on routine chest films as bilateral hilar adenopathy- May present with peripheral lymphadenopathy, cutaneous lesions, eye involvement, splenomegaly, or

hepatomegaly- Most commonly: insidious onset of respiratory abnormalities (shortness of breath, cough, chest pain,

hemoptysis) or of constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, night sweats)Evolution: unpredictable

- Progressive chronicity or periods of activity interspersed with remissions or permanent disease- May be spontaneous or induced by steroid therapy- 65% to 70% of affected patients recover with minimal or no residual manifestations- 20% have permanent loss of lung function or permanent visual impairment- 10% to 15% may die of cardiac or central nervous system damage- Most dye with progressive pulmonary fibrosis and cor pulmonale

Smoking-related interstitial diseases- Obstructive diseases: emphysema and chronic bronchitis- Restrictive or interstitial diseases

- Many individuals with idiopathic pulmonary fibrosis are smokers- Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-associated interstitial lung

disease represent two ends of a spectrum of smoking-associated interstitial lung diseases

DIFFUSE PULMONARY HEMORRHAGE SYNDROMESClassificationGoodpasture syndromeIdiopathic pulmonary hemosiderosisVasculitis-associated hemorrhage: hypersensitivity angiitis, Wegener granulomatosis, lupus erythematosus

Goodpasture syndromeDefinition: uncommon autoimmune disease in which kidney and lung injury are caused by circulating

autoantibodies against the noncollagenous domain of the α3 chain of collagen IV, which initiateinflammatory destruction of the basement membrane in renal glomeruli and pulmonary alveoli

Effects: proliferative, usually rapidly progressive glomerulonephritis and a necrotizing hemorrhagic interstitialpneumonitis

M>F, young (< 20 years), commonly in smokersPathogenesis- The trigger that initiates the anti–basement membrane antibodies is unknown

- Viral infection? Exposure to hydrocarbon solvents? Smoking?- Genetic predisposition: HLA-DRB1*1501 and *1502PathologyThe lungsMacroscopy: heavy, with areas of red-brown consolidationMicroscopy: Focal necrosis of alveolar walls associated with intra-alveolar hemorrhages Intraalveolar hemosiderin-laden macrophages In later stages: fibrosis of the septae, hypertrophy of type II pneumocytes, and organization of blood in

alveolar spaces Immunofluorescence: linear deposits of immunoglobulins along the basement membranes of the septal

wallsThe kidneys: focal proliferative glomerulonephritis in early cases or crescentic glomerulonephritisImmunofluorescence: linear deposits of immunoglobulins and complement are along the glomerular basement

membranes


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Clinical features- Hemoptysis- Xrays: focal pulmonary consolidations- Nephritic syndrome → rapidly progressive renal failure- !! The most common cause of death is uremia

PULMONARY INFECTIONSThe Pneumonia Syndromes (Robbins, 8th ed)COMMUNITY-ACQUIRED ACUTE PNEUMONIA- Streptococcus pneumoniae- Haemophilus influenzae- Moraxella catarrhalis- Staphylococcus aureus- Legionella pneumophila- Enterobacteriaceae (Klebsiella pneumoniae) and Pseudomonas spp. COMMUNITY-ACQUIRED ATYPICAL PNEUMONIA- Mycoplasma pneumoniae- Chlamydia spp. (C. pneumoniae, C. psittaci, C. trachomatis)- Coxiella burnetii (Q fever)- Viruses: respiratory syncytial virus, parainfluenza virus (children); influenza A and B (adults); adenovirus (military

recruits); SARS virusHOSPITAL-ACQUIRED PNEUMONIA- Gram-negative rods, Enterobacteriaceae (Klebsiella spp., Serratia marcescens, Escherichia coli) and Pseudomonas spp.- Staphylococcus aureus (usually penicillin resistant)ASPIRATION PNEUMONIA- Anaerobic oral flora (Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus), admixed with aerobic bacteria

(Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa)CHRONIC PNEUMONIA- Nocardia- Actinomyces- Granulomatous: Mycobacterium tuberculosis and atypical mycobacteria, Histoplasma capsulatum, Coccidioides immitis,

Blastomyces dermatitidis NECROTIZING PNEUMONIA AND LUNG ABSCESS- Anaerobic bacteria (extremely common), with or without mixed aerobic infection- Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes, and type 3 pneumococcus (uncommon) PNEUMONIA IN THE IMMUNOCOMPROMISED HOST- Cytomegalovirus- Pneumocystis jiroveci- Mycobacterium avium-intracellulare- Invasive aspergillosis- Invasive candidiasis- “Usual” bacterial, viral, and fungal organisms (listed above)

COMMUNITY-ACQUIRED ACUTE PNEUMONIAS (BACTERIAL PNEUMONIAS)Pathogenesis: bacterial invasion of the lung parenchyma causes the alveoli to be filled with an inflammatoryexudate, thus causing consolidation of the pulmonary tissue.Route of infection:

- Respiratory- Hematogenous

Forms of the disease:- Lobar pneumonia- Bronchopneumonia


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Lobar pneumoniaDefinition: fibrinosuppurative consolidation of a large portion of a pulmonary lobe or of an entire lobeEtiology: Streptococcus Pneumoniae (Pneumococcus) – most commonlyEpidemiology: pneumococcal pneumonia is commonly seen in young adults after exposure to cold or afterprevious respiratory infection. It typically follows a viral infection, often influenza.Pathology- Four stages of evolution (clinical, radiological, pathological):

- Congestion- Red hepatization- Gray hepatization- Resolution

- Morphology may be modified with antibiotherapy- One or more lobes may be affectedCongestion: days 1-2Macroscopy:- The lobe is heavy, boggy, and redMicroscopy:- Alveolar capillaries (dilated capillaries): explain the red color- Alveolar spaces:

- Edema fluid- Few neutrophils- Numerous bacteria

Red hepatization: days 2-4Macroscopy:- Consolidation of the alveolar spaces- The lobe is red, firm and airless, with a liver-like consistency → the term hepatizationMicroscopy:- Alveolar capillaries are congested- Alveolar spaces:

- Filled with fibrin which extends from an alveolus to another- Neutrophils- Bacteria- Red blood cells

Gray hepatization: days 4-6Macroscopy:- Consolidation of the alveolar spaces- The lobe is grayish-brown, firm and airless, with a dry surfaceMicroscopy:- Capillary blood flow is reduced (they are compressed by the alveolar exudate)- Alveolar spaces:

- Progressive degradation of the red cells (explains the brown color)- Persistence of the fibrino-neutrophilic exudate- Fewer bacteria

Resolution: days 7-9Macroscopy:- Consolidation disappearsMicroscopy:- Alveolar spaces:

- Contraction of the meshwork of fibrin → air enter the alveoli- Progressive enzymatic digestion of the exudate (neutrophils, macrophages) → transformed into

granular, semifluid debris that will be resorbed, ingested by macrophages, or expectoratedEvolution: uncomplicated lobar pneumonia heals without any damage of the parenchyma !!!


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Complications of pneumoniaPleuritis (pleurisy)

- Very common; some authors consider that is a feature of pneumonia, not a separate complication- Parapneumonic pleuritis: accompanies pneumonia

- Serous pleuresy- Fibrinous pleuritis:

- Is often present in the early stages if the consolidation extends to the surface- Evolution of the exudate

- Resorbtion- More often it undergoes organization, leaving fibrous thickening or permanent

adhesions- Metapneumonic pleuresy: occurs at the end of the pneumonia or after pneumonia

- Commonly purulent- More severe than the parapneumonic pleurisy- May lead to empyema (intrapleural suppurative reaction)

Abscess formation- Common with type 3 pneumococci, Klebsiella, or Staphylococcus aureus infections- Results from the lytic action of neutrophils

Organization of the exudate: fibrinous exudate is transformed into a granulation tissue and then to afibrous scar (carnification)

Bacteremic dissemination to the heart valves, pericardium, brain, kidneys, spleen, or joints, causingmetastatic abscesses, endocarditis, meningitis, or suppurative arthritis

Clinical features of lobar pneumonia- Malaise, fever, productive cough- Pleuritic pain and friction rub if fibrinous pleuritis occurs- Crackles during congestion and resolution phases- Dullness to percussion, increase tactile and vocal fremitus, egophony, bronchial breath sounds during

consolidation phases (hepatization)- ! The clinical picture is markedly modified by the administration of antibioticsRadiologic features: radiopaque infiltrate involving the entire lobe

BronchopneumoniaDefinition: patchy exudative consolidation of lung parenchyma due to terminal bronchiolitis withconsolidation of peribronchial alveoliEtiology: staphylococci, streptococci, pneumococci, H. influenzaeEpidemiology:- Common in hospitalized patients- May occur as a complication of other diseases:

- In children: diphtheria, measles, whooping cough- In adults: influenza

- Often affects two extremes of life: infants and elderly- Predisposing factors:

- Chronic retention of bronchial secretions: cystic fibrosis, chronic bronchitis, obstructing tumor, immobilepatients

- Loss of cilia function: hereditary disorders (Kartagener syndrome), squamous metaplasia, cigarette smoking,gas exposure

- Functional macrophage deficiencies: alcohol, tobacco, oxygen therapyPathogenesis:- There is initial terminal bronchiolitis (broncho-) with patchy consolidation of peribronchial lung tissue

(pneumonia)- Bronchioles are plugged by the swollen mucosa and their secretion → air cannot enter the alveoli- The imprisoned air in the alveoli is absorbed causing collapse of the alveoli- Collapsed areas are surrounded by areas of compensatory emphysema


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PathologyMicroscopy:- Bilateral (less often unilateral), gray-red, patchy consolidation with intervening normal lung tissue- Nodular, elevated, edematous to hemorrhagic-purulent areas- Lesion is more extensive at the base of the lung and often fuses together resembling lobar pneumonia(confluent bronchopneumonia)Microscopy:- Patchy lesions, separated by normal parenchyma- Blood vessels are congested- Suppurative bronchiolitis: pus and desquamated epithelium are present within the lumen and the

bronhchial wall is infiltrated with neutrophils (bronchocentric lesion)- Peribronchial lung alveoli are consolidated with fibrino-neutrophilic exudate- Compensatory emphysema in surrounding parenchyma

Evolution, complications: the same as with lobar pneumonia (but bronchopneumonia is more severe thanlobar pneumonia)

Clinical and radiological features: similar with those of the lobar pneumonia, but because the lesions arepatchy, with normally aerated intervening parenchyma, there are no:- Dullness on percution- Bronchial breath sounds- Lobar radiopaque infiltrateEvolution, complications of bronchopneumonia: see lobar pneumonia

COMMUNITY-ACQUIRED ATYPICAL (VIRAL AND MYCOPLASMAL) PNEUMONIASDefinition: acute febrile respiratory disease characterized by patchy inflammatory changes in the lungs,largely confined to the alveolar septa and pulmonary interstitiumThe term atypical refers to the following traits:- No response to the usual antibiotic treatment- Moderate amount of sputum- No physical findings of consolidation- Lack of alveolar exudateEtiology: usually involved in upper respiratory tract infection (the common cold); sometimes determine amore severe lower respiratory tract infection- Mycoplasma pneumoniae: most commonly, usually in children and young adults- Viruses: influenza virus types A and B, the respiratory syncytial viruses, measles, adenovirus, rhinoviruses,

rubeola, varicella viruses, SARS virus- Chlamydia pneumoniae- Coxiella burnetii (Q fever)Risk factors: extremes of age, malnutrition, alcoholism, and underlying debilitating illnessesPathogenesis:- Attachment of the organisms to the upper respiratory tract epithelium followed by necrosis of the cells and

an inflammatory response- When the process extends to the alveoli there is usually interstitial inflammation, but there may also be

some outpouring of fluid into alveolar spaces, so that on chest X-ray the changes may mimic bacterialpneumonia

- Damage to and denudation of the respiratory epithelium inhibit mucociliary clearance and predispose tosecondary bacterial infections

Pathology: all the etiologic agents determine the same patterns of lesionsMacroscopy:- The lung involvement may be patchy or whole lobes bilaterally or unilaterally may be affected- Affected areas are red-blue and congested, subcrepitant- The pleura is smooth (pleuritis or pleural effusions are infrequent)


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Microscopy: the histologic pattern depends on the severity of the disease- Patchy or lobar areas of congestion without consolidation- Predominance of interstitial inflammation (pneumonitis): widened edematous alveolar wall containing

mononuclear inflammatory cells (lymphocytes, macrophages, rarely plasma cells)- Alveolar spaces:

- May be free or with exudate- Pink hyaline membranes may line the alveolar - when interstitial pneumonia is complicated byARDS (acute respiratory distress syndrome) - diffuse alveolar damage

- Characteristic viral cytopathic changes may be present (viral inclusions, cytomegaly, etc.)- Superimposed bacterial infection is common and may change the histologic picture: ulcerative bronchitis,

bronchiolitis, and bacterial pneumonia

Clinical course:- The clinical course is extremely varied: from severe upper respiratory tract infections to chest colds- Cough may be absent- The ordinary sporadic form of the disease is usually mild with a low mortality rate- Interstitial pneumonia may assume epidemic proportions with intensified severity and greater mortality (see

influenzal pandemics or smaller epidemics)

LUNG TUMORSThe great majority of cases are carcinomas

LUNG CARCINOMAEpidemiology:- The most frequently diagnosed major cancer in the world- The most common cause of cancer mortality worldwide- M>F- 40-70 years of ageEtiopathogenesis:- Cigarette-smoking- Industrial hazards: high-dose ionizing radiation is carcinogenic, uranium, asbestos (lung cancer is the most

frequent malignancy in individuals exposed to asbestos, particularly when coupled with smoking)- Air pollution: radon (e.g., in homes in areas of high radon in soil)- Genetic factors:

- Molecular genetics:- Dominant oncogenes that are frequently involved in lung cancer: c-MYC, KRAS, EGFR,

c-MET, c-KIT- Commonly deleted or inactivated tumor suppressor genes: p53, RB1, p16(INK4a)

- Occasional familial clustering has suggested a genetic predisposition- 25% of lung cancers worldwide arise in nonsmokers and are pathogenetically distinct:

- Occcur more commonly in women- Most are adenocarcinomas- Tend to have EGFR mutations, and almost never have KRAS mutations and p53 mutations

Classifcation:- Squamous cell carcinoma (M: 32%; F: 25%)- Adenocarcinoma (M: 37%; F:47%)- Small cell carcinoma (M:14%; F: 18%)- Large cell carcinoma (M:18%; F:10%)


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1. Squamous cell carcinomaDefinition: malignant epithelial tumor of the lung showing squamous differentiation- M>F- Closely correlated with a smoking history- Shows the highest frequency of p53 mutations of all histologic types of lung carcinoma- Location:- Central region of the lungs, from the segmental or subsegmental bronchi- Incidence of peripherally located tumors is now increasingPrecursor lesions: squamous metaplasia, dysplasia, carcinoma in situ (this may last for several years); by thistime, atypical cells may be identified in cytologic smears of sputum or in bronchial lavage fluids or brushings,although the lesion is asymptomatic and undetectable on radiographs.Paraneoplastic syndrome: hypercalcemiaMicroscopy: characterized by the presence of keratinization and/or intercellular bridges

2. AdenocarcinomaDefinition: malignant epithelial tumor with glandular differentiation or mucin production by the tumor cells- The incidence of adenocarcinoma has increased significantly in the last two decades- It is the most common form of lung cancer in women and nonsmokers- KRAS mutation is a common finding, especially in smokersLocation: at the periphery of the lungMicroscopy:- Various patterns: acinar, papillary, bronchioloalveolar, and solid with mucin formation- Cells are immunohistochemically positive for thyroid transcription factor-1 (TTF-1) and about 80% contain

mucin

Bronchioloalveolar carcinoma- Distinct form of adenocarcinoma- Location: at the periphery, originating from terminal bronchioloalveolar regions of the lungPathologyMacroscopy:- Single nodule or, more often, as multiple diffuse nodules that sometimes coalesce to produce a pneumonia-

like consolidation- The nodules:- May have a mucinous, gray translucence when secretion is present or- Appear as solid, gray-white areas that can be confused with pneumonia on gross inspectionMicroscopy:- Pure bronchioloalveolar growth pattern with no evidence of stromal, vascular, or pleural invasion- The key feature: tumor cells growth along preexisting structures without destruction of alveolar

architecture- Two histological subtypes: nonmucinous and mucinous

Evolution and prognosis:- Nonmucinous bronchioloalveolar carcinoma:

- Consists of a peripheral lung nodule- Aerogenous usually absent- May be removed surgically- Excellent 5-year survival

- Mucinous bronchioloalveolar carcinoma:- Tend to spread aerogenously, forming satellite tumors- May present as a solitary nodule, as multiple nodules, or an entire lobe may be consolidated by

tumor (resembling lobar pneumonia)- Are less likely to be cured by surgery


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3. Small cell carcinomaDefinition: highly malignant tumor of neuroendocrine origin- Have a strong relationship to cigarette smoking- M>F- There is no known preinvasive phase or carcinoma in situ- The most aggressive form of lung cancer, virtually incurable by surgical means- It is the lung cancer most commonly associated with ectopic hormone production (ADH, ACTH)- C-myc oncogene and p53 and Rb1 tumor suppressor genes are frequently mutatedLocation:- Central, most commonly, in major bronchi- May be located in the periphery of the lungPathologyMacroscopy:- Central/hilar; white-tan, soft, friable, with extensive necrosis- Peripheral nodules have fairly well-defined border and fleshy cut surfaceMicroscopy:- Small tumoral cells, round, oval, or spindle-shaped with scant cytoplasm and ill-defined cell borders- Nuclei have finely granular chromatin (salt and pepper pattern), and absent or inconspicuous nucleoli- The cells grow in clusters that exhibit neither glandular nor squamous organization- Necrosis is common and often extensive- There are numerous mitoses- Electron microscopy shows cytoplasmic dense-core neurosecretory granules- Immunohistochemistry: cells are positive for neuroendocrine markers (chromogranin, synaptophysin, CD57)

4. Large cell carcinomaDefinition: undifferentiated malignant epithelial tumor that lacks the cytologic features of small-cellcarcinoma and glandular or squamous differentiation- M>F; Highly aggressive- Probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they

can no longer be recognized by light microscopyVariant: large cell neuroendocrine carcinoma

5. Combined carcinomaApproximately 10% of all lung carcinomas have a combined histology (two or more of the above types)

General features of lung carcinomas- Origin:

- Arise most often in and about the hilus of the lung; usually these tumors are squamous cell or smallcell carcinomas- The tumors located at the periphery of the lung arise from the alveolar septal cells or terminalbronchioles; usually these are adenocarcinomas

- Growth:- At the beginning, the tumor growths and obstructs the lumen of a major bronchus, often producing

distal atelectasis and infection- Subsequently, the tumor may follow a variety of paths:

- It may continue to fungate into the bronchial lumen to produce an intraluminal mass- It can also rapidly penetrate the wall of the bronchus to infiltrate along the peribronchial tissue

into the adjacent region of the carina or mediastinum- The tumor grows along a broad front to produce a cauliflower-like intraparenchymal mass that

appears to push lung substance ahead of it


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- Macroscopy:- In almost all patterns the neoplastic tissue is gray-white and firm to hard- In large tumor, secondary modifications can occur:

- Focal areas of hemorrhage or necrosis- Cavitation

- Tumors may erode the bronchial epithelium and can be diagnosed by cytologic examination of sputum,bronchoalveolar lavage fluid, or fine-needle aspiration

- Local extension: to the pleural surface and then within the pleural cavity or into the pericardium- Metastases:

- Spread to the tracheal, bronchial, and mediastinal nodes can be found in most cases- Distant spread of lung carcinoma occurs through both lymphatic and hematogenous pathways:

- Tumors often spread early throughout the body except for squamous cell carcinoma,which metastasizes outside the thorax

- Metastasis may be the first manifestation of an underlying occult pulmonary lesion- No organ or tissue is spared- More common distant sites:

- Adrenal glands: are involved in more than half the cases- Liver, brain, bone

- First choice treatment:- Surgery, for non-small cell carcinomas- Chemotherapy: for small cell carcinomas

- Prognosis:- Generally, 5-year survival is15%; better for bronchioloalveolar carcinoma- Adenocarcinoma and squamous cell carcinomas tend to remain localized longer and have a slightly better

prognosis than do the undifferentiated cancers, which are usually advanced by the time they are discovered

Clinical course of the lung carcinoma- One of the most insidious and aggressive neoplasms- Most commonly discovered in patients over 50 years of age- Symptoms are of several months' duration: cough (75%), weight loss (40%), chest pain (40%), and dyspnea(20%)- Not infrequently the tumor is discovered by its secondary spread during the course of investigation of anapparent primary neoplasm elsewhere- Bronchioloalveolar carcinomas, by definition, are noninvasive tumors and do not metastasize; unlessresected, they kill by suffocation.

Local Effects of Lung Tumor Spread (Robbins, 8th ed)Clinical Feature Pathologic basisPneumonia, abscess, lobar collapse Tumor obstruction of airwayLipoid pneumonia Tumor obstruction; accumulation of cellular lipid in foamy macrophagesPleural effusion Tumor spread into pleuraHoarseness Recurrent laryngeal nerve invasionDysphagia Esophageal invasionHemoptysis Bronchial erosion, tumor necrosisDiaphragm paralysis Phrenic nerve invasionRib destruction Chest wall invasionSuperior vena cava syndrome SVC compression by tumorHorner syndrome Sympathetic ganglia invasionPericarditis, tamponade Pericardial involvement


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Paraneoplastic syndromes- Some of them are determined by the hormones or hormone-like factors elaborated by the tumor cells:(Robbins, 8th ed)

Substance EffectAntidiuretic hormone (ADH) Hyponatremia ( inappropriate ADH secretion)Adrenocorticotropic hormone (ACTH) Cushing syndromeParathormone, parathyroid hormone-related peptide,prostaglandin E, and some cytokines

Hypercalcemia

Calcitonin HypocalcemiaGonadotropins GynecomastiaSerotonin and bradykinin Carcinoid syndrome

- Other: acanthosis nigricans, dermatomyositis/polymyositis, multifocal progressive encephalopathy

CARCINOID TUMOR- Also called well-differentiated neuroendocrine carcinoma- <5% of primary lung tumors- Locally invasive, rarely metastasizes- Usually ages 40 years or younger; no gender predilection, not related to smoking- Occasionally occurs as part of MEN (multiple endocrine neoplasia) syndrome- May infiltrate or spread to local lymph nodes, but doesn’t affect prognosis- Rarely produces carcinoid syndrome (flushing, diarrhea, cyanosis)- 10 year survival is 50%- In children, involve lung or liver, may metastasize regardless of histology or classification- Macroscopy: either central (polypoid and endobronchial in major bronchi) or peripheral (solid/nodular);

usually well defined, smooth, ivory to pink cut surface, no necrosis- Microscopy:- Nests or trabeculae of medium sized polygonal cells of low nuclear grade, round to oval finely granular

nuclei and lightly eosinophilic cytoplasm- May have rosettes or small acinar structures with variable mucin- Scanty vascular stroma

PLEURAL TUMORS

Solitary fibrous tumor of the pleura (“benign mesothelioma”)Definition: soft-tissue tumor with a propensity to occur in the pleura and, less commonly, in the lung, as wellas other sitesSynonyms: “benign mesothelioma”, “benign fibrous mesothelioma” in the pleura and “fibroma” in the lungEtiology: it has no relationship to asbestos exposurePathologyMacroscopy:- Often attached to the pleural surface by a pedicle- Small (1 to 2 cm in diameter) or may reach an enormous size- Tends to remain confined to the surface of the lung- Dense white fibrous tissue with occasional cysts filled with viscid fluidMicroscopy:- Whorls of reticulin and collagen fibers among which are interspersed spindle cells resembling fibroblastsBehavior: most commonly it is a benign tumor


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Malignant mesotheliomaDefinition: primary malignant tumor of the pleuraEtiology: exposure to asbestos, after a long latent period of 25 to 45 years. There is no increased risk ofmesothelioma in asbestos workers who smoke. This is in contrast to the risk of asbestos-related lungcarcinoma, which is markedly magnified by smoking. Thus, for asbestos workers (particularly those who arealso smokers), the risk of dying of lung carcinoma far exceeds that of developing mesotheliomaPathologyMacroscopy:- Arises from either the visceral or the parietal pleura- Growths diffusely and spreads widely in the pleural space- It is usually associated with extensive pleural effusion and direct invasion of thoracic structures- The affected lung becomes ensheathed by a thick layer of soft, gelatinous, grayish pink tumor tissueMicroscopy:- Histological subtypes: epithelioid (60%), sarcomatoid (20%) - monophasic, or mixed (20%) - biphasic- The epithelioid type:

- Resembles adenocarcinoma- May be difficult to differentiate grossly and histologically from pulmonary adenocarcinoma- Immunohistochemical positivity for calretinin favors the diagnosis of mesothelioma

- The sarcomatoid type resembles fibrosarcoma- The mixed type contains both epithelioid and sarcomatoid patternsEvolution- Direct extension to the lung- Metastatases to the hilar lymph nodes and, eventually, to the liver and other distant organsPrognosis: 50% of patients die within 12 months of diagnosis, and few survive longer than 2 years

!!!! Mesotheliomas also arise in the peritoneum, pericardium, tunica vaginalis, and genital tract. Peritonealmesothelioma is related to heavy asbestos exposure

logy lecture chapter 1 - pathology of the respiratory tract 2010-2011

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