Path Respiratory System II (16)

• a group of lung diseases that affect the interstitium (the tissue & space around the air sacs of the lungs)
• they restrict lung movement during respiration & are characterized predominantly by diffuse & usually chronic involvement of the pulmonary connective tissue, especially the most peripheral & delicate interstitium in the alveolar walls
• also known as diffuse parenchymal lung disease (DPLD)
• Restrictive or Infiltrative can be substituted for Interstitial

• reduced compliance
• more pressure is required to expand the lungs b/c they are stiff → ↑ effort to breath (dyspnea)

1. Hypoxia: an abnormal ventilation-perfusion ratio due to damage of the alveolar epithelium & interstitial vasculature

• 2. Chest radiograph irregularities: small nodules or “ground-glass shadows” (irregular lines)
• -there's density in the lung NOT due to liquid

3. Diffuse interstitial fibrosis w/ or w/o “honeycombing” (severe cases)

• a lung condition defined by the presence of small cystic spaces w/ irregularly thickened walls composed of fibrous tissue
• dense fibrosis causes alveolar walls to collapse → formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchial epithelium
• as the connective tissue thickens, it's able to be visualized in a radiograph
• 

• Alveolitis
• inflammation & progressive thickening of the walls of the air sacs of the lungs results in shortness of breath

• MACROPHAGES
• activated macrophages (+ other inflammatory & immune effector cells) accumulate within alveolar walls & spaces in an attempt to digest/get rid of whatever is causing any alveolitis
• *this a key event in the pathogenesis of interstitial fibrosis
• 

• if the injury is mild, it's self-limiting & the tissue can be restored back to its normal architecture
• if the parenchyma is severely injured fibroblasts proliferate → progressive interstitial fibrosis
• this arises from persistence of the injurious agents & cellular interactions involving lymphocytes, macrophages, & neutrophils

• based on either their clinicopathologic syndromes or by their characteristic histology
• the condition can vary from minimally symptomatic, severely incapacitating, & sometimes lethal due to overwhelming interstitial fibrosis

• 1. Idiopathic Pulmonary Fibrosis (Cryptogenic Fibrosing Alveolitis) - itself is a classification
• 2. Usual Interstitial Pneumonia (UIP)
• 3. Pneumoconiosis (eg. Asbestosis)

• a group of restrictive lung diseases of UNKNOWN etiology
• is caused by ‘repeated cycles’ of epithelial activation/injury by some UNIDENTIFIED agent
• abnormal epithelial repair gives rise to exuberant fibroblastic or myofibroblastic proliferation → FIBROBLASTIC FOCI [too much of a good thing]
• lung tissue from people w/ IPF shows a characteristic radiographic & histopathologic pattern: UIP

• TGF-β1 (transforming growth factor)
• produces a patchy, BILATERAL interstitial fibrosis
• in advanced cases this results in severe hypoxemia & cyanosis
• 

• a form of lung disease characterized by progressive scarring (fibrosis) of the interstitium of both lungs
• the basic underlying pathology is FIBROSIS (not inflammation)
• is the pathologic counterpart of Idiopathic Pulmonary Fibrosis

• COBBLESTONE APPEARANCE of pleural surface (due to retraction of scars along the interlobular septa
• cut surface shows FIBROSIS (firm, rubbery white areas) especially in the LOWER lobe
• distributes distinctively in the subpleural region & along the interlobular septa
• 

• patchy chronic inflammation & interstitial fibrosis of VARYING intensity
• normal lung can exist next to fibrotic areas
• early: fibroblastic foci (lots of fibroblastic proliferation)
• later: foci are more COLLAGENOUS & LESS cellular
• early & late lesions coexist (temporal heterogeneity)
• honeycomb fibrosis
• patchy interstitial inflammation contains alveolar septal infiltration of mostly LYMPHOCYTES (sometimes plasma cells & eosinophils)

• 1 of the most common types of interstitial lung disease
• begins w/ gradual dyspnea on exertion & dry cough (crackles during inspiration), usually over a period of 1 to 3 yrs
• in later stages cyanosis, cor pulmonale, & peripheral edema may develop
• only therapy: lung transplantation

• an occupational & restrictive lung disease caused by the inhalation of dust
• happens when a non-neoplastic lung reacts to the inhalation of mineral dusts or organic & inorganic particulates

• 1. Coal Worker’s Pneumoconiosis (anthracosis/black lung/miner's lung) is due to coal/carbon
• 2. Silicosis is due to silica
• 3. Asbestosis is due to asbestos

• MOST IMPORTANT FACTOR: the capacity of the inhaled dusts to stimulate fibrosis
• depends on the size, shape, solubility, & reactivity of the particles
• particles that are 1-5μ are the most dangerous b/c they can get lodged at bifurcations of distal airways
• the pulmonary MACROPHAGE response to an irritant is what initiates & perpetuates lung injury & fibrosis
• Tobacco smoking worsens the effects of all inhaled mineral dusts (especially w/ ASBESTOS)
• particles are removed using mucociliary clearance

• is VERY fibrogenic*
• includes a group of fibrous silicate minerals that exist as long fibers
• has been used for insulation & construction materials
• 1. Serpentine asbestos (Chrysotile): curly, flexible fibers that account for the bulk of commercially used asbestos
• 2. Amphibole asbestos: straight, stiff, brittle fibers that are less prevalent but MORE pathogenic

• bilateral diffuse interstitial fibrosis resulting from inhalation of asbestos fibers
• requires heavy exposure to asbestos
• the fibers deposit in distal airways, bronchioles, within alveolar spaces, & especially at BIFURCATIONS of alveolar ducts
• MACROPHAGES engulf small particles but larger fibers penetrate into the interstitium
• activated macrophages release inflammatory mediators + the fibrogenic character of the free asbestos fibers in the interstitium → interstitial pulmonary fibrosis
• 

Alveolitis

• e/a is a clear, thin, asbestos fiber surrounded by a beaded iron-protein coat that is golden brown in routine sections
• stains strongly with PRUSSIAN BLUE (a stain for IRON)
• macrophages coat asbestos fibers w/ protein, proteoglycans, & ferritin
• 

• 1. parenchymal interstitial fibrosis (asbestosis)
• 2. localized fibrous plaques or diffuse pleural fibrosis (more rare)
• 3. pleural effusions
• 4. lung cancer (bronchogenic carcinomas)
• 5. malignant pleural & peritoneal mesotheliomas
• 6. laryngeal cancer

• Cigarette smoking
• family members of workers exposed to asbestos are also at an increased risk for cancer

• 1. Hypersensitivity Pneumonitis (Allergic Alveolitis)
• 2. Sarcoidosis

• an inflammation of the ALVEOLI within the lung caused by hypersensitivity to inhaled organic dusts
• 1st type III & then type IV hypersensitivity occur
• is a Restrictive lung disease w/ ↓ diffusion capacity, lung compliance, & total lung volume
• eg. Farmer's Lung (actinomycetes in mouldy hay), Bird Fancier's Disease (bird droppings), Byssinosis (cotton dust)

• loosely formed interstitial granulomas & chronic inflammation
• 

• when macrophages - in certain cases of chronic inflammation - collect in layers surrounding the problematical material (silica, or TB, etc) & fuse, forming giant cells
• structure = layers of macrophages surrounding a central core

• occurs in farmers turning hay b/c organisms called actinomycetes are present in mouldy hay
• repeated inhalation of these organisms stimulates systemic IgG antibody production
• further inhalation produces immune complexes in the lung & an Arthus (localized) reaction
• LATER T-cells infiltrate w/ cytokine production → further inflammation
• *therefore this is a mixture of Type III & Type IV hypersensitivity reactions

• a multi-system disease of unknown etiology characterized by NON-CASEATING granulomas in tissue & organs, usually in the LUNGS & lymph nodes
• caused by a systemic type IV hypersensitivity reaction against an unknown antigen driven by CD4+ helper T cells
• occurs more commonly in African Americans (10:1 caucasians)
• is a form of chronic Interstitial (Restrictive) lung disease
• is a disease of disordered immune regulation in genetically predisposed persons exposed to certain environmental agents

• e/a is a discrete, compact collection of epithelioid cells rimmed by an outer zone of largely CD4+ T cells
• remember epithelioid cells = activated, flattened macrophages
• 

1. granulomas scattered in the interstitium, along the pleura, interlobular septa & around bronchovascular bundles in the lung

• 2. multinucleated giant cells
• 

3. laminated fibroblasts around the granuloma

• 4. Asteroid bodies (star-shaped crystals)
• 

• 5. Schaumann bodies (calcifications)
• 
• #4 & #5 seen IN the granuloma

• diffuse interstitial fibrosis (thus, a form of chronic interstitial/restrictive lung disease)
• the lungs are involved in 90% of patients
• in 75% of patients who receive a lung transplantation, sarcoidosis returns
• other organs (lymph nodes, skin, eyes, liver, spleen) are also affected

• classified according to etiology (bacterial, viral, fungal), location of the lesion (alveolar or interstitial), or extent of lung involvement (diffuse, focal, unilateral, or bilateral)
• Community-Acquired Acute Pneumonia (Streptococcus pneumoniae, Haemophilus influenzae)
• Community-Acquired Atypical Pneumonia (Mycoplasma pneumoniae)
• Aspiration Pneumonia
• Chronic Pneumonia
• Necrotizing Pneumonia & Lung Abscess
• Pneumonia in Immunocompromised Host

• 1. bronchopneumonia
• 2. lobar pneumonia
• 
• 

• caused by Streptococcus pneumoniae, is the most common cause of community-acquired acute pneumonia especially in:
• 1. those with underlying chronic diseases (eg. COPD, CHF, diabetes)
• 2. those w/ congenital or acquired immunoglobulin defects
• 3. those with decreased or absent splenic functions

• lobar or broncho may occur
• the LOWER or RIGHT MIDDLE lobes are involved most frequently
• can involve the entire or almost entire lobe
• complete restoration of the lung is the rule for both forms of pneumococcal pneumonia w/ appropriate therapy

• 1. congestion
• 2. red hepatization
• 3. gray hepatization
• 4. resolution
• 

• affected lobes are heavy, red, & boggy
• blood vessels become congested w/ proteinaceous fluid, scattered NEUTROPHILS, & lots of bacteria in the lumen

• after a few DAYS, the lungs develop a liver-like consistency
• the alveolar spaces are packed w/ NEUTROPHILS, red blood cells, & fibrin
• [fibrin: a fibrous, non-globular protein formed from fibrinogen by thrombin that polymerizes to form a "mesh" that plugs/clots a wound]
• 
• congested septal capillaries
• EXTENSIVE NEUTROPHIL exudation into alveoli
• (fibrin net has NOT YET formed)

• the lung becomes dry, gray, & firm b/c RBCs have lysed
• at this stage fibrinosuppurative EXUDATE persists in the alveoli [fibrin aka protein + pus aka WBCs]

• this stage only follows in uncomplicated cases
• is when exudate in alveoli are enzymatically digested to produce granular, semifluid debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it

early treatment with antibiotics

• PATCHES: inflammatory foci are distributed in patches throughout 1 or several lobes bilaterally & basally
• lesions can grow up to 3 or 4 cm in diameter
• reaction consists of focal suppurative exudate that fills the bronchi, bronchioles, + adjacent alveolar spaces

• abscess
• empyema
• organization of the intra-alveolar exudate may convert areas of the lung into solid fibrous tissue
• bacteremic dissemination → meningitis, arthritis, or infective endocarditis

the lung is a frequent site for metastasis of cancers from other sites & primary tumors & lung cancers (are the leading cause of cancer deaths in the US)

• the Bronchial epithelium
• the remaining 5% include bronchial carcinoids, mesenchymal malignancies, lymphomas, & a few benign lesions (eg. hamartomas)

• 1. Squamous cell carcinoma
• 2. Adenocarcinoma
• 3. Large cell carcinoma
• 4. Small cell carcinoma
• these are classified into 2 broad groups: small cell lung cancer (SCLC) & non-small-cell lung cancer (NSCLC) for therapeutic purposes

• b/c virtually all SCLCs have metastasized by the time they're diagnosed, therefore they're NOT curable via surgery
• SCLCs are best treated by chemotherapy w/ or w/o radiation
• NSCLC are best treated w/ surgery (& usually respond poorly to chemotherapy)

• injury to the bronchial epithelium (eg. from cigarette smoking) is followed by metaplasic regeneration from the pluripotent basal layer → dysplasia → carcinoma in situ → invasive tumor
• is similar to SCC in other sites lined by squamous epithelium (eg. cervix, skin)
• most often arises CENTRALLY in LARGER bronchi
• is closely associated w/ smoking & responsible for 30% of all invasive lung cancers in the US
• 
• usually begins as central (hilar) masses & grow contiguously into the peripheral parenchyma
• squamous cell carcinoma can undergo cavity necrosis during intrapulmonary spread

• meta/dysplasia can exist YEARS before an invasive tumor develops
• 

• usually arises in the PERIPHERY & is often associated with pleural fibrosis + subpleural scars which can result in pleural puckering
• tumors grow slowly
• tumors tend to metastasize at an EARLY stage
• it's responsible for 1/3 of all invasive lung cancers in the US (more than SCC)

Adenocarcinoma of the Lung

• Acinar
• Papillary
• Mucinous
• Solid

• Atypical Adenomatous Hyperplasia (AAH)
• it's a well-demarcated focus of epithelial proliferation composed of cuboidal to low- columnar cells resembling Clara cells or type 2 pneumocytes
• these cells show various degrees of cytologic atypia but not to the extent seen in Adenocarcinomas
• AAH progresses to Adenocarcinoma in situ (< 3cm) → minimally invasive Adenocarcinoma → invasive Adenocarcinoma

• AAH: mild interstitial fibrosis is seen along w/ cuboidal epithelium
• 

• Adenocarcinoma: GLANDULAR structures; droplets of mucin may be found within the tumor cell cytoplasm
• 

• undifferentiated malignant epithelial tumors that lack the glandular or squamous differentiation & cytologic features of small-cell carcinoma
• cells have large nuclei, prominent nucleoli, & a moderate amount of cytoplasm
• most likely evolve from either poorly differentiated adenocarcinomas or squamous cell carcinomas
• accounts for ~10% of invasive lung tumors
• 

• may have neuroendocrine features (eg. neuroendocrine granules seen under EM or IHC staining positive for chromogranin or synaptophysin)
• is a highly MALIGNANT epithelial tumor that grows & metastasizes rapidly
• when 1st seen 70% of patients are already in an advanced stage
• STRONGLY associated w/ cigarette smoking
• accounts for 20% of all lung cancers

• as pale gray, centrally located masses w/ extension into the lung parenchyma & early involvement of the hilar & mediastinal lymph nodes [~in the lung]
• exist as sheets of small, round, oval or spindle-shaped cells w/ little cytoplasm & distinctive nuclei that have finely granular nuclear chromatin & an absent nucleoli
• cells have a high rate of mitosis
• necrosis in the tumor is often seen & can be extensive

• Small Cell Carcinoma
• it's the conformity of adjacent cell nuclei to one another that results from close apposition of tumor cells that have little cytoplasm
• the feature is useful when differentiating between small cell carcinoma & non-small cell carcinomas (i.e. adenocarcinoma & squamous carcinoma)

• it's sensitive to chemotherapy but will invariably recur
• median survival even w/ treatment is 1 year

• 3% - 10%
• 1. Hypercalcemia, secretion of parathyroid hormone-related peptide
• 2. Cushing syndrome, increased production of ACTH
• 3. Syndrome of inappropriate secretion of antidiuretic hormone
• 4. Neuromuscular syndromes, including a myasthenic syndrome, peripheral neuropathy, & polymyositis
• 5. Clubbing of finders & hypertrophic pulmonary osteoarthropathy
• 6. Hematologic manifestations

• Squamous Cell Carcinoma : Hypercalcemia
• Adenomas : Hematological Syndromes
• Small Cell Carcinoma : everything else

• CENTRALLY located low-grade malignant tumors composed of neuroendocrine cells that arise from Kulchitsky (Enterochromaffin) cells which line the bronchial mucosa
• resemble intestinal carcinoids
• appear at an early age (~40 yrs) & represent about 5% of all pulmonary tumors
• are not related to cigarette smoking & appear equally in males & females
• 

• contain dense-core neurosecretory granules in the cytoplasm
• most are endocrinologically silent & rarely secrete hormonally active polypeptides
• those affected exhibit Carcinoid Syndrome: intermittent attacks of diarrhea, flushing, & cyanosis (serotonin, kallikrein)
• often resectable & curable
• 
• small, rounded, uniform nuclei & moderate cytoplasm

• the array of symptoms that occur secondary to Carcinoid tumors which causes endogenous secretion of serotonin
• characterized by flushing, hypOtension, diarrhea, & right heart failure (serotonin is inactivated in the lung & therefore does't affect the left side of the heart)

• neoplasm of mesothelial cells that is most common in the pleura but can also occur in the peritoneum, pericardium, & the tunica vaginalis of the testis
• is associated w/ asbestos exposure (latency period btwn exposure & appearance is ~20 yrs)
• cigarette smoking + asbestos exposure DOESN'T ↑ mesothelioma risk
• tumor cells often encase & compress the lung, extending into fissures & interlobular septa → ‘pleural rind’

• pulmonary parenchyma invasion is generally limited to the periphery adjacent to the tumor
• lymph nodes tend to be spared
• average age of patients: 60 years
• tumor spreads locally within chest cavity,
• invading & compressing major structures
• there is extensive pleural FIBROSIS & PLAQUE formation
• metastasis to hilar lymph nodes, liver, & distant organs can occur

treatment is largely ineffective, prognosis is poor, it is invariably lethal within 2 years