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Interstitial Lung Diseases (ILD)
- 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
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What is the hallmark of Interstitial Lung Diseases?
- reduced compliance
- more pressure is required to expand the lungs b/c they are stiff → ↑ effort to breath (dyspnea)
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Other Interstitial Lung Diseases Characteristics
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)
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Honeycombing
- 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

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What is the earliest common manifestation of most of the interstitial diseases?
- Alveolitis
- inflammation & progressive thickening of the walls of the air sacs of the lungs results in shortness of breath
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Activation of which immune cell type commonly leads to/is a precursor of interstitial diseases?
- 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

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Mild vs. Parenchymal Alveolitis
- 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
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How are Interstitial Lung Diseases classified?
- 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
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Types of Interstitial Lung Diseases
- 1. Idiopathic Pulmonary Fibrosis (Cryptogenic Fibrosing Alveolitis) - itself is a classification
- 2. Usual Interstitial Pneumonia (UIP)
- 3. Pneumoconiosis (eg. Asbestosis)
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Idiopathic Pulmonary Fibrosis (Cryptogenic Fibrosing Alveolitis)
- 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
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What factor plays a role in the characteristic fibroblastic proliferation/fibroblastic foci of Idiopathic Pulmonary Fibrosis?
- TGF-β1 (transforming growth factor)
- produces a patchy, BILATERAL interstitial fibrosis
- in advanced cases this results in severe hypoxemia & cyanosis

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UIP (Usual Interstitial Pneumonia)
- 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
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Gross Characteristics of UIP
- 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

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Histological Characteristics of UIP
- 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)
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Clinical Features of UIP
- 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
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Pneumoconiosis
- 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
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Depending upon the type of dust, pneumoconiosis is given different names:
- 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
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Pneumoconiosis Pathogenesis
- 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
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Asbestos
- 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
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Asbestosis
- 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

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What is the FIRST lesion that is directly associated with asbestos exposure?
Alveolitis
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Asbestos Body in the Lung
- 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

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What are the 6 disease processes linked to asbestos exposure?
- 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
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What increases the risk of lung cancer in the setting of asbestos exposure?
- Cigarette smoking
- family members of workers exposed to asbestos are also at an increased risk for cancer
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Types of Granulomatous Diseases
- 1. Hypersensitivity Pneumonitis (Allergic Alveolitis)
- 2. Sarcoidosis
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Hypersensitivity Pneumonitis (Allergic Alveolitis)
- 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)
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What histologically characterizes Hypersensitivity Pneumonitis (allergic alveolitis)?
- loosely formed interstitial granulomas & chronic inflammation

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Granuloma
- 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
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Farmer’s Lung
- 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
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Sarcoidosis
- 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
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Non-caseating Granuloma
- 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

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Cellular Characteristics of Sarcoidosis
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
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What eventually replaces the granulomas characteristic of Sarcoidosis?
- 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
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Pulmonary Infections
- 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
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What are the 2 types of Pneumonia?
- 1. bronchopneumonia
- 2. lobar pneumonia
 
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Pneumococcal 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
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Pneumococcal Pneumonia Morphology
- 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
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What are the 4 stages of the LOBAR pattern of pneumonia?
- 1. congestion
- 2. red hepatization
- 3. gray hepatization
- 4. resolution

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1. Congestion
- affected lobes are heavy, red, & boggy
- blood vessels become congested w/ proteinaceous fluid, scattered NEUTROPHILS, & lots of bacteria in the lumen
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2. Red Hepatization
- 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)
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3. Gray Hepatization
- 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]
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4. Resolution
- 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
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What alters or halts the typical progression of Pneumococcal Pneumonia?
early treatment with antibiotics
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Bronchopneumonic Pneumococcal Pneumonia Morphology
- 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
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What are possible complications of Pneumococcal Pneumonia?
- 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
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Pulmonary Neoplasms
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)
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What is the site of origin for 95% of primary lung tumors (carcinomas)?
- the Bronchial epithelium
- the remaining 5% include bronchial carcinoids, mesenchymal malignancies, lymphomas, & a few benign lesions (eg. hamartomas)
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What are the 4 major histologic types of carcinomas of the lung?
- 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
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Why are the 4 major histologic types of lung carcinomas classified into 2 groups?
- 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)
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Squamous Cell Carcinoma (SCC) of the Lung
- 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
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How long before an invasive tumor is detectable may precursor lesions of squamous cell carcinomas exist?
- meta/dysplasia can exist YEARS before an invasive tumor develops

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Adenocarcinoma of the Lung
- 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)
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What is the most common form of lung cancer in women & NONsmokers?
Adenocarcinoma of the Lung
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What are the possible histological subtypes of Adenocarcinoma of the Lung?
- Acinar
- Papillary
- Mucinous
- Solid
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What is thought to be the precursor of peripheral Adenocarcinoma?
- 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
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Atypical Adenomatous Hyperplasia vs. 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

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Large-Cell Carcinoma
- 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

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Small Cell Carcinoma of the Lung
- 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
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How do Small Cell Carcinoma tumors appear?
- 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
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‘Nuclear molding’ is characteristic of what type of cancer?
- 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)
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How does Small Cell Carcinoma respond to chemotherapy?
- it's sensitive to chemotherapy but will invariably recur
- median survival even w/ treatment is 1 year
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What percentage of patients with lung cancers develop clinically overt paraneoplastic syndromes?
- 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
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Match Each Paraneoplastic Syndrome with it's Lung Cancer*
- Squamous Cell Carcinoma : Hypercalcemia
- Adenomas : Hematological Syndromes
- Small Cell Carcinoma : everything else
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Bronchial Carcinoids
- 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

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Bronchial Carcinoid Tumor Cells
- 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
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Carcinoid Syndrome
- 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)
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Malignant Mesothelioma
- 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’
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Mesothelioma Characteristics
- 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
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How is Malignant Mesothelioma treated?
treatment is largely ineffective, prognosis is poor, it is invariably lethal within 2 years
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