Pathology Flashcards
What is the etiology of lung cancers occurring in non smokers?
More common in women
Most adenocarcinomas
Tend of have EGFR and not KRAS mutations
What is the relationship between smoking and lung cancers?
11% of heavy smokers will develop lung cancer
Squamous and small cell carcinomas show strongest association with tobacco
Moderate association with adenocarcinoma and large cell carcinoma
What are central vs. peripheral tumors?
Central - squamous cell, small cell carcinomas
Peripheral - adenocarcinoma, large cell carcinoma
How are lung cancers divided based on histology?
Non small lung cell - 75-80% - metastases at diagnosis common - treated surgically if resectable
Small cell - almost always metastases at diagnosis, responsive to chemotherapy, RB mutations common
What gene mutations are seen in adenocarcinomas?
KRAS mutations
EGFR mutations - Asians, women, non smokers
ALK rearrangements - non smokers, signet ring morphology
Which lung neoplasms have no association with smoking?
Bronchial carcinoids
Mesotheliomas
What are the basics of squamous cell carcinoma?
Men more than women, smokers
Large lesions with central necrosis
Slower to form distant metastases than other types but can spread to hilar lymph nodes
Central tumors - close to trachea or bronchi
What is the pathology of squamous cell carcinoma?
Keratinization (squamous pearls)
Intercellular bridges
Tadpole cells with red cytoplasm
What is the pathogenesis of squamous cell carcinoma?
Preceded by metaplasia and dysplasia then carcinoma in situ
Higher frequency of p53 mutations
Precursor lesions = goblet cell hyperplasia, basal cell hyperplasia, squamous metaplasia
What is an adenocarcinoma?
Malignant epithelial tumor with glandular differentiation and/or mucin production
Distant metastasis early in course but slow growth
Acinar, papillary, or solid pattern
What is the pathogenesis of adenocarcinoma?
Atypical adenomatous hyperplasia - bronchioloalveolar carcinoma - invasive adenocarcinoma sequence
Mutations and amplifications of EGFR (mostly in women, non smokers, Chinese) - can be treated with tyrosine kinase inhibitors
KRAS mutations has resistance to TK inhibitors and worse prognosis
What is adenocarcinoma in situ (bronchioloalveolar carcinoma)?
Grows in monolayer in lepidic pattern along alveolar septa without invasion or destruction of architecture
3 cm or less in size
Nonmucinous - single nodule, amenable to surgery, excellent prognosis
Mucinous - satellite nodules, less cured by surgery
What is atypical adenomatous hyperplasia?
Pre neoplastic lesion of small (<.5 cm) focus of type 2 pneumocystis proliferation with mild cytologic atypia
What are the basic features of large cell carcinoma?
Undifferentiated malignant epithelial tumor
Large cells with vesicular nuclei, prominent nucleoli, no obvious glandular or squamous differentiation
Mostly diagnosis of exclusion - malignant and poor prognosis
What is the pathogenesis of small cell carcinoma?
P53 and RB mutations
Arises from neuroendocrine cells
No Pre invasive or carcinoma in situ phase
What is the pathology of small cell carcinoma?
Main stem bronchi with early involvement of hilar and mediastinal nodes
Small cells with scant cytoplasm, finely granular chromatin, inconspicuous nucleoli
Prominent nuclear molding and crush artifact
Azzopardi effect - Nuclear material from crushed cells cling to blood vessels and cause them to stain blue on H&E
What are bronchial carcinoids?
Rare well differentiated neuroendocrine tumors
Young and non smokes
Resectable and curable
Carcinoid syndrome - diarrhea, flushing, cyanosis - may be present
Rosette formation - uniform cells with regular nucleus, salt and pepper chromatin, are mitosis and no necrosis
Typical carcinoid - atypical carcinoid - small cell continuum
What are paraneoplastic syndromes associated with lung cancers?
Small cell carcinoma - ACTH and ADH production - Cushing’s and SIADH
Squamous cell carcinoma - PTH like hormone - hypercalcemia
Gonadotropins - gynecomastia
Serotonin and bradykinin - carcinoid syndrome
What are associated presentations of lung cancers?
Vena caval syndrome (upper lobe lesions)
Horner syndrome - ptosis, pupil constriction, anhydrosis
Pancoast syndrome - pain in distribution of ulnar nerve due to brachial or cervical sympathetic plexus invasion
What are the most frequent metastases to the lung?
Breast
Colon
Kidney
What is the most common cause for pleural effusion?
CHF - Transudative effusion
What are the most common cause of exudative effusions?
Microbial infections
Cancer
Pulm infarction
Viral pleuritis
How do pleural effusions resolve?
Transudative tend to resorb once cause alleviated
Exudative can lead to fibrinous organization and eventual scarring of pleural surfaces, sometimes calcification
What is mesothelioma?
Rare cancer of mesothelial cells arising in parietal or visceral pleura
Common association with asbestos exposure - incubation can be 25 yrs or more
Some association with SV40 DNA virus - t antigen can bind and inactivate p53 and RB
What are the different types of asbestos fibers?
Serpentine - chrysotile - flexible, more common, low oncogenicity
Amphibole - crocidolite - brittle, less prevalent, more oncogenic
Asbestos bodies = asbestos fibers coated with iron rich material found in lungs
What is the immunohistochemistry of mesothelioma?
Stain with calretinin and CK 5/6
Adenocarcinomas stain with MOC31 and CEA
What is the pathology of mesothelioma?
Lung becomes ensheathed by thick fleshy tumor
Can have pleural effusions
Epithelioid and spindle (sarcomatoid) cell types
Can form papillary, tubular, or glandular structures resembling adenocarcinoma - differentiate with immunohistochemistry
What is Samter’s triad?
Asthma
Nasal polyps
Aspirin sensitivity
All cause excess leukotrienes
What are nasal polyps?
Benign Outgrowth of nasal mucosa
Associated with chronic rhino sinusitis, asthma, allergies, CF
Intact mucosa overlying edematous and inflamed lamina propria
What is sinonasal papilloma?
Benign tumor of sinonasal mucosa - arises in squamous or columnar epithelium of sinonasal tract
3 types - exophytic/septal, endophytic/inverted (can be locally aggressive and recur, grows inward from surface, lateral walls), cylindrical
Low risk HPV types (6, 11) associated
Treatment is surgical excision
What is nasopharyngeal angiofibroma?
Benign mesenchymal, highly vascular tumor - bleeds excessively
Seen in adolescent boys - testosterone driven
Locally aggressive - may invade bone and recur
Numerous thin walled blood vessels in cellular fibrous stroma
Treatment is surgical excision
What is nasopharyngeal carcinoma?
Common in adult Chinese and pediatric African population
Strong association with EBV
3 histologic patterns - keratinizing squamous cell, non keratinizing squamous cells, undifferentiated (large epithelial cells in syncytium pattern with heavy lymphocytic infiltrate = lymphoepithelioma)
Treatment is radiotherapy with/without chemo
What are necrotizing lesions of nose and UR tract?
Acute infections - fungus esp in diabetics, tb, immunocompromised
Vasculitis - wegener
Cocaine abuse
Neoplastic
What are vocal cord nodules/polyps?
Smoking or voice abuse
Small protrusions in vocal cord
Benign squamous epithelium overlying edematous myxoid stroma
May spontaneously regress, can be surgically excised
What is laryngeal papilloma?
Benign neoplasm
Multiple and bilateral in children, adults can have single lesion
Often recur
Small raspberry like masses on true vocal cord
Squamous epithelium lined finger like projections with central fibromuscular cores
Associated with HPV 6, 11
What is carcinoma of the larynx?
More common in men over 40
Associated with smoking, alcohol, asbestos, irradiation, HPV
Most are squamous cell
Clinically presents as hoarseness
Begin as pearly plaques of SCC in situ - ultimately infiltrates, ulcerates, and fungates
Treatment is surgery, radiation or combo - prognosis better in organ confined disease, 1/3 die
What is the field effect?
Cigarette smoking exposes multiple areas to carcinogens and these patients often develop multiple SCCs in upper and lower respiratory tracts
What is the relationship between HPV and head and neck squamous carcinomas?
Over half infected with high risk HPV, esp 16
HPV tumors less likely to have p53 mutations
HPV positive patients better overall and disease specific survival
More common in sinonasal papillomas, laryngeal papillomas, squamous carcinomas
What is atelectasis and what are the three types?
Collapse of previously inflated lung
3 types - resorptive/obstructive (complete obstruction with absorption of air in distal airway, mediastinum shifts toward source, reversible), compressive (external force compresses lung, mediastinum shifts away, reversible), contraction (fibrosis prevents expansion, mediastinum shifts toward source, irreversible)
What is the hallmark of obstructive lung disease?
FEV1/FVC ratio <80%
What are the different types of obstructive lung diseases?
Acute and reversible - asthma
Chronic and irreversible - COPD, bronchiectasis
What is the definition of emphysema?
Permanent enlargement of air space distal to terminal bronchioles accompanied by destruction of septal walls and without fibrosis
Exhalation cause collapse, inhalation not largely affected
What are the different patterns of emphysema?
Centriacinar/centrilobular - proximal part of acini (respiratory bronchioles), upper lobes, most common, primarily smokers
Panacinar/panlobular - entire acinus, lower lobes, alpha 1 antitrypsin deficiency
Distal acinar - sub pleural, cysts called bullae can cause PTX
Irregular - isolated airway distension from scarring, asymptomatic
What is the pathogenesis of emphysema?
Loss of elasticity, inflammation and thickening of small bronchiolar walls due to smooth muscle hypertrophy and fibrosis Excess proteases (elastase) over anti protease (alpha 1 antitrypsin) - nicotine activates former and inhibits latter, genetic deficiency of alpha 1 antitrypsin Excess oxidants (free radicals) over anti oxidants (superoxide dismutase, glutathione) - nicotine can do this
What is the clinical presentation of emphysema?
Pink puffers - over ventilate and are well oxygenated
Breathing through pursed lips
Barrel chest and weight loss
Hepatic cirrhosis with alpha 1 antitrypsin
Hyperinflation
Infrequent exacerbations
What are three complications of emphysema?
Pulm HT and cor pulmonale - increased resistance in PAs
Respiratory failure
Tension PTX - from rupture of bullae
What is the definition of chronic bronchitis?
Persistent productive cough for a least 3 consecutive months in at least 2 consecutive years
What is the pathogenesis of chronic bronchitis?
Primary cause is smoking and air pollutants
Inflammatory cells - cd8 T cells and neutrophils
What happens in large and small airways in chronic bronchitis?
Large - hypersecretion of mucin, hypertrophy of submucosal glands
Small - goblet cell metaplasia, mucus plugging, inflammation and fibrosis
Damaged cilia
What are the clinical presentations of chronic bronchitis?
Blue bloaters - hypoxia and hypercapnia
Long history of cough and sputum
Frequent exacerbations
Decreased respiratory rate, deep and laborious breathing
What are complications of chronic bronchitis?
Pulm HT and cor pulmonale
Dev of COPD
Cellular atypia/dysplasia can progress to carcinoma
What is the definition of bronchial asthma?
Chronic inflammatory disorder of airways characterized by recurrent, episodic, reversible bronchoconstriction of hyperactive airways in response to various stimuli
Expiratory wheezing and prolongation of expiration
What are the three different types of asthma?
Atopic/extrinsic - allergic type 1 hypersensitivity reaction, starts as child, igE, family hx, environmental stimuli
Non atopic/intrinsic - not hypersensitivy, non immune stimuli, no family hx, normal igE, common in adults
Drug induced - aspirin can change balance of leukotrienes
What is the pathogenesis of non atopic asthma?
Viral inf and inhaled air pollutants are common triggers
Inflammation of respiratory mucosa lowers threshold of subepithelial vagal receptors to irritants
What is status asthmaticus?
Severe asthma persisting for days, resistant to therapy
Extensive desquamation of cilia and epithelium which impedes removal of mucus
What is the morphology of asthma?
Gross hyper inflated lungs with areas of atelectasis
Mucus plugs in bronchi and bronchioles - contain curschmanns spirals of shed epithelium, entrapped eosinophils, and Charcot-Leyden crystals
What processes make up the airway remodeling in asthma?
Basement membrane thickening
Edema and inflammation (eosinophils and mast cells)
Increased sub mucosal glands and mucous metaplasia of epithelium
Increased vascularity
Bronchiolar wall thickening from muscle hypertrophy and hyperplasia
What is the definition of bronchiectasis?
Permanent dilation of bronchi and bronchioles caused by destruction of smooth muscle and supporting elastic tissue associated with chronic necrotizing infections
What are predisposing conditions for bronchiectasis?
Bronchial obstruction - foreign body, tumors, mucus impact on
Congenital - CF, immunodeficiencies, kartagener syndrome
Necrotizing pneumonia - m. Tb, s. aureus, aspergillus
What is the pathogenesis of bronchiectasis?
Two processes critical - either can come first
Obstruction
Chronic persistent necrotizing infection
What is the morphology of bronchiectasis?
Lower lobes typically more affected
Abnormal dilation of distal airways can get to pleural surface
What are the clinical presentations of bronchiectasis?
Severe persistent cough with foul smelling expectorant
Possibly Hemoptysis
Clubbing of fingers (pulmonary osteoarthropathy)
What are the complications of bronchiectasis?
Pulm HT
abscess formation in brain or lung
Amyloidosis
What are the two major categories of restrictive lung diseases?
Chest wall disorders with normal lungs - neuromuscular, obesity
Parenchymal diseases of lung - ARDS, chronic types
What is the definition of ARDS?
Acute life threatening respiratory insufficiency due to diffuse alveolar epithelial and vascular damage
Typically within 24-48 hrs following initiating event
Profound hypoxemia
What are the four main causes of ARDS?
Sepsis
Diffuse pulm inf/pneumonia
Gastric aspiration
Severe mechanical trauma with shock (head injuries)
What is the pathogenesis of ARDS?
Imbalance between pro and anti inflammatories
Neutrophils recruited by macrophage signaling
Activated neutrophils release mediators –> Endothelial and epithelial injury - edema fluid, surfactant loss from necrosis of type II pneumocytes, hyaline membranes from leaking exudate into alveoli
What is the morphology and clinical course of ARDS?
Gross heavy dark red, airless lungs
Acute phase - intra alveolar edema and hyaline membrane formation, flu like symptoms progressing to severe dyspnea, refractory to oxygen therapy, mechanical ventilation
Organizing stage - proliferation of type 2 pneumocytes and progressive interstitial fibrosis, may progress to multiorgan failure, patients may recover but have chronic fibrosis
What are chronic restrictive lung diseases?
Parenchymal fibrosis leads to restriction of lung expansion
Dyspnea and hypoxia
CXR show ground glass shadows
Surgical biopsy is gold standard for diagnosis
Decreased gas exchange
What are possible complications of chronic restrictive lung diseases?
Respiratory failure - end stage is honeycomb lung
Pulmonary HT
cor pulmonale
What is the pathogenesis of chronic restrictive lung diseases?
Repeated cycles of acute lung injury and wound healing
Activated macrophages recruit neutrophils that release mediators resulting in pneumocyte injury and over active repair
Macrophages also secrete mediators of wound healing that cause fibrosis
What is idiopathic pulmonary fibrosis?
Most common chronic interstitial lung disease
Unknown etiology
Older males more
Insidious onset and slow inexorable progression and marked interstitial fibrosis, resp failure in 3-4 yrs
What is the pathology of idiopathic pulmonary fibrosis?
Cobblestone lung surface
Usual interstitial pneumonia pattern - patchy interstitial fibrosis with sub pleural accentuation
Temporal heterogeneity - fibrosis alternates with normal lung
Honeycomb lung
Variable lymphocytic infiltratives
Reticular appearance on imaging and peripheral distribution
How is idiopathic pulmonary fibrosis diagnosed and treated?
Surgical lung biopsy is gold standard
Only treatment is transplant
What is nonspecific interstitial pneumonia?
Similar to UIP but diffuse and treatable
Associated conditions - collagen vascular disease (SLE), drug reaction, chronic renal failure
CT has ground glass opacified and fibrosis but no honey combing
Two histologic phases - cellular and fibrotic
What is cryptogenic organizing pneumonia?
Response to lung injury
Temporally uniform polyploid masses of myxoid fibroblasts tissue in peripheral airways and alveoli
Diagnosis by biopsy
Steroids for long periods allows most patients recovery
What are pneumoconioses?
Non neoplastic lung reaction to inhalation of organic and inorganic particulates
Most important agents are coal dust, silica asbestos, beryllium
What are factors in the development of pneumoconioses?
Amount of dust retained in lung - concentration in air, duration of exposure, clearance mechanisms
Size and shape, solubility, toxicity of inhaled particles
Tobacco smoking worsens all effects
What is coal workers pneumoconiosis?
Coal in lungs - at least 10 yrs before manifesting
More prominent in upper lobes
What are the varieties of severity in coal workers pneumoconiosis?
Asymptomatic anthracosis - least severe, carbon accumulates in macrophages with no cell reaction
Simple - accumulation of macrophages, mild fibrosis, associated emphysema, stops progressing when exposure stops
Complicated/progressive - extensive fibrosis, black scar larger than 2 cm, no increased risk of carcinoma, progressive after exposure has ceased
Nodules worse than macules
What is silicosis?
Inhalation of silicon dioxide
Common in rock miners, sandblasters and pottery workers
Usually upper lobes - usually mild but can be severe
Increased risk for TB
Crystalline forms more toxic than amorphous
What is the morphology of silicosis?
Multiple discrete hard pale blue or green nodules - collagenous with whorled configurations
Possible central necrosis from TB
Concentric hyalinized collagen with dust laden macrophages in periphery
Egg shell calcification in hilar lymph nodes
What are the clinical features of silicosis?
Asymptomatic with normal lung function tests
Shortness of breath develops late
Caplan’s syndrome - lung diseases in patients with silicosis and rheumatoid lung disease
What are benign and malignant asbestos induced diseases?
Benign - pleural plaque or effusion, parenchymal interstitial fibrosis
Malignant - bronchogenic carcinoma, mesothelioma, laryngeal cancer
What are pleural plaques?
Most common manifestation of asbestos exposure
Dense fibrosis of pleura - plaques of collagen
No effect on lung function, no asbestos bodies seen, no association with lung cancer
What is the morphology of asbestosis?
Similar pattern to UIP - lower lobes and sub pleural
Asbestos bodies - golden brown rods with translucent exposure
Can lead to honeycomb lung
Usually detected incidentally on CXR
Dyspnea 10-20 yrs after exposure
What is smoking related interstitial disease and the two types?
Desquamative interstitial pneumonia (DIP) - diffuse accumulation of pigmented macrophages, ground glass pattern
Respiratory broncholitis-associated interstitial lung disease (RB-ILD) - patchy and have bronchogenic distribution
Excellent response to steroids and cessation of smoking
What is sarcoidosis?
Non caseating granulomas in many organs
Bilateral hilar adenopathy
Diagnosis of exclusion - unknown etiology, disordered immune regulation
Women more than men, African descent more common
What are important lab features of sarcoidosis?
Elevated ACE
hypercalcemia
Decreased circulating cd4 lymphocytes
What is the pathology of sarcoidosis?
Schaumann bodies - laminated concretions of calcium and proteins
Asteroid bodies - eosinophilic stellate inclusions within giant cells
What is hypersensitivity pneumonitis?
Immune mediated type III and type IV hypersensitivity interstitial lung disorder caused by hypersensitivity to inhaled organic dust antigens such as moldy hay
What is the pathology of hypersensitivity pneumonitis?
Patchy lymphocytic infiltrate with peribronchial accentuation and mild fibrosis
Non caseating granulomas
Reticular infiltrates and ground glass opacities
Rarely progresses to honeycomb lung
What is the definition of pulm HT?
Pulm BP reaches 1/4 (normal is 1/8) systemic BP
What are common causes of pulm HT?
Chronic obstructive or interstitial lung disease
Recurrent pulm emboli
Heart disease –> mitral stenosis and l to r shunts
Idiopathic
What is the pathogenesis of pulm HT?
Decreased production of vasodilators (prostacyclin and NO) and increased release of vasoconstrictors (endothelin)
Migration and replication of smooth muscle cells
Tgf beta pathway abnormality
Loss of BMPR2 signaling –> more proliferation
What are plexiform lesions?
Tufts of capillary formation filling lumens of arteries
Seen in severe cases of pulm HT
What are diffuse alveolar hemorrhage syndromes?
Primary immune mediated diseases with triad of hemoptysis, anemia, and diffuse pulmonary infiltrates
Include goodpasture syndrome, idiopathic pulmonary hemosiderosis, wegeners
What is goodpasture syndrome?
Anti glomerular basement membrane antibodies
Interstitial pneumonitis and glomerulonephritis
Intra alveolar hemorrhage and hemosiderin in alveoli
Ig deposition along septa
What is idiopathic pulm hemosiderosis?
Mostly children, unknown etiology
Similar to goodpasture but no Ig or renal involvement
Milder course and full remission
What is wegeners granulomatosis?
Systemic necrotizing vasculitis in upper and lower respiratory tracts and glomerulonephritis
C-ANCA
Fever, bloody nasal discharge, nasal ulcers, hemoptysis, hematuria, polyarthralgias
