Lung Head and Neck

Nonneoplastic Lung Pathology Lung Anatomy • Anatomy: Usually 3 lobes on the right, 2 on left (with lingula on left rather than a middle lobe). • Right mainstem more vertical than left, therefore, aspiration more common on right. • Bronchi extend from the trachea; progressive branching of the bronchi forms bronchioles (no cartilage or submucosal mucous glands); further branching of bronchioles to terminal bronchioles; the acinus is composed of respiratory bronchioles, alveolar ducts, and alveolar sacs. • Except for the vocal cords (squamous epithelium), the entire respiratory tree (larynx, trachea and bronchioles) is lined by pseudostratified tall columnar ciliated epithelium • Goblet cells in surface epithelium and mucus secreting submucosal glands are also present, except for the bronchioles. • Neuroendocrine cells are also present. Lung Histology • Alveolar histology: Air – alveolar macrophages - alveolar epithelium - basement membrane/interstitium - capillary endothelium – blood. • Basement membrane composed of collagen, elastic fibers, fibroblast-like interstitial cells, smooth muscle cells, mast cells, and rare lymphocytes and monocytes. • Alveolar epithelial cells are 95% type I pneumocytes (flattened for gas exchange) and 5% type II (rounded, produce surfactant and are important in repair). • Alveolar macrophages are derived from blood monocytes, may contain carbon, hemosiderin. • Alveoli communicate directly to one another via pores of Kohn Pulmonary edema • Secondary to hemodynamic disturbances or increase capillary permeability (microvascular injury) • Most common hemodynamic cause is due to increased capillary pressure due to left sided congestive heart failure. • Gross: Heavy, wet lungs. • Micro: – Acute: Pink, granular, proteinaceous fluid in airspaces. – Chronic: Hemosiderin-laden macrophages (“heart failure cells”). • Long standing cases may have fibrosis and thickening of the alveolar walls. • Generally don’t get biopsy for this – evaluate thru CXR. Acute pulmonary edema  Adult respiratory distress syndrome • Adult respiratory distress syndrome: Injury to the alveolar capillary membrane leading to accumulation of edema fluid and hyaline membranes lining the alveoli. • Pathogenesis different than newborn hyaline membrane disease (surfactant deficiency). • Numerous etiologies: Sepsis, viral infection, Mycoplasma, Pneumocystis, aspiration, trauma, near drowning, fat emboli, burns. • ARDS patients are usually already hospitalized for another cause, 60% mortality. • Hyaline membranes formed from inspissation of protein rich edema fluid and entrapped dead alveolar epithelial cells. • >50% of ARDS cases associated w/sepsis, diffuse pulmonary infections, aspiration and mechanical trauma/head injuries • Micro: The hyaline membranes are composed of edema fluid with fibrin and remnants from dead cell membranes. There is type II pneumocyte proliferation and eventual fibrosis and thickening of the alveolar septae. – Get thickened, basement membrane-ish material lining alveolar spaces • Activation of Nuclear factor-kB initiates pro-inflammatory cytokines (IL-8, IL-1, and TNF), which activate neutrophils which then release leukotrienes, oxidants, proteases and platelet-activating factors that cause tissue damage and reaction. Later, additional factors initiate fibroblasts and collagen formation. – Endotoxin has been described as more common trigger for this, but underlying mech (regardless of how it started – head injury, infection, etc.) is related to activation of NF-kB.

1: Hyaline membranes in ARDS. 2: ARDS (note hyaline membrane and type II pneumocyte hyperplasia) • Dense, thickened hyaline membranes line alveolar spaces – composed of junk that gets broken down. • Big purple cells around the edge are type II pneumocytes – become hyperplastic. • Not the same etiology as infants, but looks the same. Test q: The histologic finding in the following photograph (but none is printed on the test) is a nonspecific indicator of pulm epithelial cell injury. It is best described as: Type II pneumocyte hyperplasia. (Other choices: Ferruginous bodies, Asteroid bodies, Pulm hypertension)

Pulmonary emboli • Sole or contributing cause of death in 10% of patients dying in hospitals. • 95% from deep veins of legs. • Large emboli: End up in main pulmonary artery or at the bifurcation (saddle embolus), often causes sudden death secondary to electromechanical dissociation (ECG shows rhythm but no pulse felt) • Small emboli: Travel to peripheral vessels, if patient has adequate cardiovascular fxn, the bronchial arteries will sustain the lung parenchyma and the result is hemorrhage, but no infarction; Only about 10% of small emboli result in infarction (wedge-shaped) – Unlikely to cause death – may cause SOB, acute abnormalities. Lungs have dual blood supply, so unless patient is compromised in CV manner, it’s unlikely that these will cause true infarct. Instead, will get hemorrhagic infarct on smaller emboli. Could see real infarct if pt is CV-compromised. • CXR changes 12-36 hours later, wedge-shaped infiltrate. • Most often diagnosed with CT angiography, less often with V/Q scintigraphy, pulmonary angiography • 30% develop subsequent emboli. • Complication principally in those already suffering from some underlying disorder, such as cardiac disease, cancer, immobolization • CT scan more accessible anymore than VQ scan which requires nuclear medicine availability • Hypercoagulable states: o Primary: factor V leiden, prothrombin, antiphospholipid; o Secondary: obesity, recent surgery, cancer, oral contraceptive use, pregnancy Pulmonary hypertension (PH) • Lungs are low resistance system (1/8 of systemic); PH defined as >1/4 systemic. • PH most frequently associated with structural conditions that increase pulmonary blood flow/pressure, pulmonary vascular resistance, or left heart resistance. • Idiopathic variant most common in young women presenting with dyspnea and fatigue. • 5 clinical categories: – Pulmonary arterial hypertension - Idiopathic, Familial (BMPR2 mutation – bone morphogenetic protein receptor 2), associated with other disease, i.e. collagen vascular disease (scleroderma), congenital shunts, portal HTN, HIV, drugs (fenfluramine/phentermine – weight loss), toxins – PH with left heart disease - Atrial/ventricular/valvular disease – PH with lung disease/hypoxemia - COPD, Interstitial lung disease, sleep apnea, developmental lung disease – PH with chronic thrombotic and/or embolic disease – Miscellaneous • Pathologic features: – Medial hypertrophy of muscular/elastic arteries – Atheromas – Right ventricular hypertrophy – Plexiform lesions (advanced disease)  Tuft of capillary formations • Constant high pressure  “Glomeruloid” appearance 

Test q: A 35F dies following a 2yr course of progressive fatigue and dyspnea. An autopsy is performed which is significant for RV hypertrophy and mildto-moderate atherosclerosis of the coronary arteries, aorta, and pulmonary artery. These findings support which of the following as a probable cause of death? Pulmonary hypertension. (Other choices: ARDS, Acute pulmonary embolus, Sarcoidosis)

Diffuse pulmonary disease • Diffuse pulmonary disease historically divided into obstructive and restrictive. • Obstructive: Increased airflow resistance (therefore, decreased FEV1). – Air can get in but hard to get out. • Restrictive: Decreased expansion of lung parenchyma (therefore, decreased total lung capacity). – Air has a hard time getting in, so TLC low. • Obstructive causes: Emphysema, chronic bronchitis, bronchiectasis, asthma. • Restrictive causes: Chest wall disorders (obesity, kyphoscoliosis, pleural disease), interstitial lung diseases. Test q: A 55M presents w/shortness of breath. Eval included pulmonary function testing which demonstrates a decreased FEV1 and normal TLC. These findings are compatible with all of the following conditions EXCEPT: Silicosis. (Other choices: Chronic bronchitis, Emphysema, Bronchiectasis, Asthma)

Emphysema • Increased distal air space size, alveolar wall destruction, lacks obvious fibrosis. • Various forms described, little clinical significance in distinguishing, 95% of cases are centriacinar (respiratory bronchioles affected much more than distal alveoli). • Common, >50% autopsy incidence, cause of death in 7%. • Etiology: – Cigarette smoking (nicotine chemotactic for neutrophils, smoking causes alveolar macrophages to release IL-8 which is also chemotactic for neutrophils, smoking stimulates neutrophils to release elastase and increases macrophage elastase activity) – a-1-antitrypsin deficiency (an inhibitor of elastase, normal PiMM 90% of population, PiZZ is most common in patients with emphysema). • Smoking also decreases the anti-oxidant mechanisms available in the lung. • Small airways are tethered by the elastic recoil of the lung parenchyma. Therefore, the loss of elastic tissue in the walls of alveoli reduces radial traction and then leads to resp. bronchiole collapse during expiration  functional airflow obstruction • Upper 2/3 of lung more severely affected: clubbing at the end of septae secondary to dilatation of pore of Kohn (bc of loss of elasticity) that make it appear as septae are free floating; blebs/bullae form with more severe disease • No increased inflammation Chronic bronchitis • Clinical definition: Persistent cough for >3 months for 2 consecutive years. • Mucus overproduction in large airways (submucosal gland hypertrophy; increased Reid index). – Hypertrophy defined as submucosal glands making up 40+% of respiratory epithelium/underlying cartilage in cross section of wall of bronchus. • Small airways: goblet cell metaplasia, mucus plugging, accumulation of pigmented macrophages. • Infection thought to be secondary, causes acute exacerbations. • Reid index= ratio of thickness of the mucous gland layer to the thickness of the wall between the epithelium and cartilage. > 0.4 abnormal • Will see inflammatory cells in the wall of bronchus Chronic bronchitis: Intraluminal and transmural inflammation  Asthma • Asthma: Chronic relapsing inflammatory disorder with hyperreactive airways associated with atopy (increased susceptibility to make IgE in response to allergens). • Increased incidence in the last 30 years.

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Extrinsic: Type I hypersensitivity (allergic/atopic asthma, occupational asthma, allergic bronchopulmonary aspergilliosis). Intrinsic: Nonimmune (aspirin, pulmonary viral infections, cold, stress, exercise). Involves many cell types and many inflammatory mediators. Atopic asthma: Type I hypersensitivity (IgE mediated). Th2-type T-lymphocytes are sensitized, release IL-4, IL-5 and IL-13 which promote IgE production by B-lymphocytes, mast cell growth, eosinophil activation. o Important to identify eosinophils in tissues of asthmatics. o Test q: A 12M has shortness of breath and wheezing in response to dust and animal dander exposure. Which of the following are important to the pathogenesis of his clinical findings? IL-4 and IL-5 production by T-cells. (Other choices: Damage to alveolar capillary endothelial cells by lipopolysaccharide, Autoantibody versus GM-CSF, A deficiency of an inhibitor of elastase)

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Mediators: Leukotrienes, acetylcholine most important (because antagonist drugs exist). Histamine, prostaglandin D2, platelet activating factor are involved, but less important. Nonatopic asthma: Viruses are provokers, also air pollution (SO2, O3, NO2), aspirin (aspirin-provoked asthma seen in patients with urticaria, rhinitis, nasal polyps), occupational agents (organic fumes, dust). Gross: Over inflated lungs, bronchial occlusion by mucus plugs. Micro: Curschmann spirals, eosinophils, Charcot-Leyden crystals, increased basement membrane thickness, enlarged submucosal gland size, increased bronchial wall muscle thickness.

1: Asthma – eosinophils. 2: Asthma – basement membrane thickening and mucus 3: Curchmann Spiral – Mucus plugs containing whorls of shed epithelium. Tissue gets embedded in mucus  spirals of mucus and epithelial cells smooshed together. 4: Charcot-Leyden crystal and degenerating eosinophils. Collections of crysliaps bintalloid made up of galectin-10 (eosinophil lysophospholipase binding protein). Crystals are made of degenerating eosinophil membranes. Test q: An 18M w/a history of asthma has been non-compliant w/his meds and is found dead at home. At autopsy, what histo findings would be expected in the lungs? Bronchial mucin plugging and increased thickness of the BM and bronchial smooth muscle layer. (Other choices: Diffuse airspace enlargement w/o significant fibrosis, Diffuse interstitial fibrosis w/an interstitial chronic inflammatory cell infiltrate, Decreased eosinophils within the lung)

Bronchiectasis: • Bronchiectasis: Permanent destruction of muscle/elastic tissue in bronchi/bronchioles secondary to chronic necrotizing infection (permanent dilatation-up to 4x normal size) • Cough, fever, sputum production. • Associated with obstruction (tumor, foreign bodies, mucus), congenital conditions (cystic fibrosis, intralobar sequestration, Kartagener syndrome (ciliary dysmotility + situs inversus)) and infection (tuberculosis, Staphylococcus) – Normally infectious process. • Usually affects lower lobes, grossly airways extend to pleural surface (nml = airways >2-3 cm from pleura) • May see acute/chronic inflammation, necrosis, squamous metaplasia Bronchiectasis associated with H. influenzae infection  Dilated bronchioles, inflammatory response.

Pulmonary infections • Bacterial • Mycobacterial • Viral and mycoplama • Fungal • Parasitic Bacterial pneumonia • Bronchopneumonia: Patchy, extension of bronchitis/bronchiolitis to lung parenchyma. • Very common, especially in infancy and old age. Often present at autopsy following extended course of heart failure or cancer. Staphylococcus, Streptococcus, Haemophilus influenzae, Pseudomonas, coliform bacteria. • Lobar pneumonia: One lobe or one part of one lobe. Lower incidence than in past. 90%+ caused by pneumococcus. Can also be other encapsulated bacteria (Klebsiella pneumoniae, Pseudomonas, Proteus). Pneumonia predisposing factors • Decreased cough reflex (coma, anesthesia, drugs, chest pain) • Decreased ciliary function (smoking, viral infections, immotile cilia syndrome) • Decreased phagocytosis by alveolar macrophages (alcohol, smoking, O2 intoxication) • Pulmonary congestion • Pulmonary edema • Accumulation of secretions (cystic fibrosis, bronchial obstruction) Bacterial pneumonia • Most common cause of death during viral influenza epidemics. • Acute pneumonia: Neutrophils in alveoli (grossly – red hepatization). – Lungs beefy, begin to look like liver. • Early organization: Intraalveolar exudate with red cells and fibrin. • Late organization: Macrophages and fibroblasts with myxoid background (gray hepatization). – Not as much neutrophils – now is clean-up crew. • May resolve or progress to fibrosis. • Complications of pneumonia: abscess formation, empyema (intrapleural fibrinosuppurative reaction) and bacteremic dissemination Lung abscess • May cavitate up to 6 cm. May have a fibrous wall if chronic. • Cough fever, foul smelling bloody or purulent sputum. • Predisposing factors: Infections (dental, sinus, bronchial), dental/oral surgical procedures, obstruction (tumor), aspiration (right > left), septic emboli (cardiac valve vegetations). • Acute inflammatory cells + necrosis of alveolar septae. – Difference between lung abscess and pneumonia: lung abscess causes necrosis of alveolar septae. Pneumo does not do this, it just causes infiltrate of neutrophils. • Most common organisms: Streptococci Staphylococcus aureus, various Gram negative rods, anaerobes (Bacteroides, Fusobacterium, Peptococcus) and less commonly fungi. Viral/mycoplasmal pneumonia • Often called “atypical pneumonia”. – Different type of presentation – may just be a slight cough. • Fever, patchy inflammatory changes in lung (especially alveolar septa and pulmonary interstitum), when disease is severe, there is typically bacterial superinfection. • Mycoplasma pneumoniae is the most common cause. • Also: Influenza A, Influenza B, respiratory syncytial virus, adenovirus, rhinovirus, corona viruses (severe acute respiratory syndrome), rubeola, varicella, Chlamydia pneumoniae, Coxiella burnetti. • Cold agglutinin titers transiently elevated in 50% of M. pneumoniae. – Can differentiate underlying etiology of viral pneumonia • Variable clinical course from asymptomatic to “chest colds” to fever and muscle ache with no cough. Less than 1% mortality, occasionally higher (influenza epidemic of 1918, SARS). Test q: A 20M has had a mild fever w/nonproductive cough, headache, and myalgia for the past week. He goes to the physician, who records a temp of 37.9C and notes erythema of the pharynx. Diffuse crackles are heard on auscultation of the lungs. A CXR shows bilateral extensive patchy infiltrates. A sputum Gram stain shows normal flora. The cold agglutinin titer is elevated. He receives a course of erythromycin therapy and his condition improves. Infection w/which of the following organisms is most likely to produce these findings? Mycoplasma pneumoniae (Other choices: Legionella pneumophila, Mycobacterium fortuitum, Nocardia asteroides, RSV.)

Pulmonary tuberculosis • Lung the usual site of primary infection. • Initial focus of infection in lung parenchyma (usually peripheral) + infected draining hilar lymph node = Ghon complex. • Most primary infections are asymptomatic, most clinical cases are secondary/reactivation. • Secondary disease occurs in 5-10% of cases. • Secondary cases are most common where there is high O2 tension (pulmonary apex). • Micro: granulomas, +/- caseating necrosis, +/- multinucleate giant cells. • Organisms not visible on H&E, difficult to find even on acid-fast bacteria stain. • Miliary TB: bacteria disseminate extend into arterial system spreading dz to other organs, i.e. liver, bone marrow, adrenal, spleen, etc. Test q: A 45M has experienced a 5kg weight loss over the past 3mo after the loss of his job. He recently developed a low grade fever and cough w/mucoid sputum production and, after 1wk, he noticed blood-streaked sputum. On phys exam, his temp is 37.7C. There are bilateral crackles in the upper lobe on auscultation of the chest. A chest radiograph shows bilateral upper lobe consolidations and focal cavitations. Which of the following diagnostic tests on a sputum sample is most warranted? Acid fast stain. (Other choices: GMS stain, Gram stain, Cytologic smear, Viral culture) Test q: A 10F who participated in a routine health screening program developed a 10mm area of induration on the left forearm 3 days after intracutaneous injection of 0.1 mL of purified protein derivative (PPD). She appears healthy. A screening chest radiograph is performed. Which of the following is most likely to be seen on the radiograph? No abnormal findings. (Other choices: Marked hilar adenopathy, Upper lobe calcificiations, Extensive opacification, Cavitary change)

1. Tuberculosis – caseating granuloma 2. Tuberculosis – positive acid-fast stain. Acid-fast: Blue is counterstain – in you zoom in closer, will see little red organisms. 3. Cryptococcus: H&E stain. Fungal organism, variably-sized, narrow-based buds. 4. Cryptococcus: GMS stain GMS highlights buds.

5. Pneumocystis (H&E stain). Foamy intraalveolar exudate with minimal inflammation. More common in HIVpositive patients and the immuno-compromised. Pink exudate in alveolar spaces – prompts us to order GMS stain (#6) 6. Pneumocystis (GMS stain). Highlights “crushed pingpong ball”-like cysts. 7. Aspergillus (H&E stain). Hyphae, necrosis, and acute inflammation in pulmonary aspergillosis. Can wall itself off – get aspergilloma. Not necessarily symptomatic.

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1. Aspergillus (PAS-LG stain). LG = light green stain – highlights septae, acute-angle branching. 2. Stronglyoidies in a bronchoalveolar lavage specimen

Diffuse interstitial lung disease: • 15% of noninfectious disease seen by pulmonologists. • Usually restrictive by PFTs. • Dyspnea, +/- cyanosis, +/- wheezing. • CXR: Diffuse infiltration by small nodules and irregular lines, may be hazy “ground glass” appearance. • May progress to right heart failure/cor pulmonale. • End stage: “honeycomb lung” due to scarring, airspace enlargement. • Causes: environmental (25%), sarcoidosis (20%), idiopathic pulmonary fibrosis (15%), rheumatologic disease (scleroderma, lupus, rheumatoid arthritis) (10%), more than 100 other causes. • Earliest pathologic change: alveolitis, leukocytes release mediators that injure parenchymal cells and cause interstitial fibrosis. 3:

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3. Bleomycin induced pulmonary fibrosis. Bleomycin – antitumor antibiotic (affects 10% who take it); drug toxicity and influx of inflammatory cells 4. Amiodarone induced pulmonary fibrosis. Amiodarone used for cardiac arrythmias (affects ~5% who take it); drug gets concentrated in the lung parenchyma  fibrotic response

Pneumoconioses • Caused by inorganic and organic dusts and vapors • Anthracosis (coal dust), silicosis, asbestosis, bereliosis (beryllium), siderosis (iron). • 1-5 micron particles (small) most dangerous. – The smaller the particle, the farther down the airway it can get trapped. If stopped earlier in the respiratory tree, can be pushed back out by the mucociliary response – not as much problems. • Caplan syndrome = nodular fibrotic and centrally necrotic lung lesions seen with coexisting pneumoconiosis and rheumatoid arthritis. • Development of pneumoconioses depends on amount of dust retained in airways; size, shape and buoyancy of the particles; particle solubility and physiochemical reactivity; and additional effects of other irritants (cigarette smoke affects mucociliary apparatus) • Smaller lung particles cause acute lung injury, larger particles lead to fibrotic collagenous pneumoconioses. • 1-5 micron can reach the terminal small airways and air sacs and settle in their linings. Test q: Lung disease resulting from exposure to all of the following airborne particulate matter would be classified as a pneumoconiosis EXCEPT: Cotton fibers. (Other choices: Silica dust, Coal dust, Asbestos, Beryllium dust)

5. Pulmonary hilar lymph node with anthracosis (black pigment) and fibrosis. 6. Same area with silica particles (white specks) with polarizing lens.

Silicosis: • Silicosis: Freshly ground quartz (SiO2) has free radicals on surface which damage cell membranes, also induces cytokine release which leads to further cell death. • Gross: Hard collagenous scars, may cavitate, may involve lymph nodes with “eggshell calcification”. • Micro: fibrosis and polarizable silica particles. • Nodular lesions are composed of concentric layers of hyalinized collagen. Test q: A 63M has had progressively worsening dyspnea over the past 10 years. He has noticed a 5kg weight loss in the past 2 years. He has a chronic cough w/minimal sputum production and no chest pain. On phys exam, he is afebrile and normotensive. A chest radiograph shows extensive interstitial disease. Pulmonary function tests show low FVC and normal FEV1/FVC ratio. Increased exposure to which of the following pollutants is most likely to produce these findings? Silica. (Other choices: Tobacco smoke, Ozone, Wood dust, CO) REPEATED x2

Coal workers pneumoconiosis: • Coal workers pneumoconiosis (CWP): Grossly anthracotic lungs and lymph nodes, centrilobular emphysema and coal macules and nodules composed of carbon-laden macrophages and collagen. o Black, heavy lungs with black lymph nodes. • May lead to complicated CWP (progressive massive fibrosis): large black scars (> 2 cm) and fibrotic lungs with marked decline in function. Asbestosis: • Asbestos leads to pneumoconiosis, but also associated with pleural fibrous plaques, pleural effusions, bronchogenic carcinoma, mesothelioma, colon carcinoma. • Two major types of asbestos: – Amphibole: straight, brittle fibers, more pathogenic. But- less common. – Serpentine: curly, flexible fibers, more common. • Mesothelioma >1000x increased risk. o Smoking does not increase the risk of mesothelioma • Synergistic with smoking to increase lung carcinoma risk: asbestos alone 5x risk, asbestos + smoking 55x risk. • Micro: Diffuse interstitial fibrosis progressing to “honeycomb lung”. • Asbestos bodies: Brown (iron-containing) beads on and invisible rod. • Fibrosis occurs as macrophages ingest particles and then emit fibrogenitic mediators and chemotactic factors. o Macrophages that attempt to ingest the fibers lay down iron, get applied to surface of asbestos fiber. Actually seeing the iron microscopically, not the asbestos fibers. Test q: A 60M has a history of amphibole asbestos exposure. This exposure is known to have a strong association w/the development of all of the following EXCEPT: Hypersensitivity pneumonitis. (Other choices: Mesthelioma, Fibrous plaques of the pleura, Bronchogenic carcinoma, Pleural effusions)

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1. Asbestos bodies 2. Asbestos-related fibrous pleural plaque. The plaques do not contain asbestos fibers – just a response to asbestos exposure. Usually seen in apex of the lung.

Sarcoidosis: • Systemic disease, idiopathic, noncaseating (non-necrotizing) granulomas in many tissues. • Granulomas suggest reaction to persistent antigen, also oligoclonal T-cell proliferation. • Giant cells may have Schaumann bodies (laminated calcific concretions) or asteroid bodies. • CXR: Bilateral lung hilar lymphadeopathy. • Diagnosis of exclusion, infectious causes of granulomatous inflammation must be excluded. • Females > males, African-Americans 10x > whites. • Varied and unpredictable clinical course: May be asymptomatic, may spontaneously recover (2/3 of patients), may have progressive decline of lung function and death (10%). • Increased CD4/CD8 ratio---process driven by CD4+ helper T cells • See giant cell formation and granulomatous forms in lymph nodes, lungs, can be very systemic. We will mainly look at it in lung.

Test q: A 61F has experienced increasing dyspnea and a nonproductive cough for 5mo. On phys exam, her temp is 37.7C. A CXR shows prominent hilar lymphadenopathy w/reticulonodular infiltrates bilaterally. A transbronchial biopsy is performed and the microscopic findings include interstitial fibrosis and small, noncaseating granulomas. One granuloma contains an asteroid body in a giant cell. The medical history indicates that she smoked cigarettes for 10yr but stopped 5yr ago. Which of the following is the most likely cause of her illness? Delayed hypersensitivity response to an unknown antigen. (Other choices: Immune complexes formed in response to an unknown antigen, Diffuse alveolar damage, Smoke inhalation for many years, Infection w/atypical mycobacteria.) Robbins explanation: The clinical and morphologic features strongly suggest sarcoidosis. This granulomatous disease has an unknown cause, but the presence of granulomas and activated T-cells in the lungs indicates a delayed hypersensitivity response to some inhaled antigen. Lung involvement, occurring in about 1/3 of cases, may be asymptomatic or may lead to restrictive lung disease.

Figure (above): Sarcoidosis (noncaseating granuloma w/giant cells). No necrosis. Sarcoidosis is a diagnosis of exclusion – must exclude everything else (e.g. microorganisms). Can’t diagnose w/just a slide. Needs to correlate w/clinical factors.

Idiopathic pulmonary fibrosis: • IPF is the clinicopathologic syndrome that correlates with the histologic pattern of UIP (usual interstitial pneumonia) o Histologic features of UIP can be seen with connective tissue disease, hypersensitivity pneumonia, asbestos o UIP = patchy interstitial fibrosis that varies in age and intensity. Fibroblastic proliferations progress to collagenous, less cellular areas. o Leads to dilated cystic spaces lined by hyperplastic pneumocytes • Intraalveolar exudates early, interstitial mononuclear cell infiltrate, then marked thickening of the interstitium by fibrosis, progresses to “honeycomb lung”. • Respiratory distress with hypoxia and cyanosis. • Median survival < 5 years. • Although true etiology is somewhat unknown, thought to be related to constant acute injury over time that leads to chronic-type response.

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1. Idiopathic pulmonary fibrosis 2. Idiopathic pulmonary fibrosis (usual type interstitial pneumonitis)

Fibrotic lungs w/cystically-dilated spaces (residual alveolar spaces). Described as a disease that varies in space and time – could have some unaffected parts of lungs, some areas that have more fibrosis or almost collagen, other areas that are more cellular. Can see type II pneumocyte hyperplastic response in cystic spaces. Alveolar septae are obliterated by fibrotic response = honeycomb lung. Test q: A 62M presents w/progressive dyspnea on exertion of 1yr duration and a dry cough. On phys exam, he is afebrile and mild digital clubbing is noted. He is a nonsmoker and history does not reveal any evidence of exposure to an environmental agent likely to be associated w/his symptoms. A lung biopsy is performed to attempt to provide a diagnosis (see below – but no picture is printed on our version of the old test). The most likely diagnosis is: Idiopathic pulmonary fibrosis (usually type interstitial pneumonia. (Other choices: Emphysema, Bronchopneumonia, Atypical pneumonia.) Test q: Which of the following is true regarding idiopathic pulmonary fibrosis (usual-type interstitial fibrosis)? The end stage has marked fibrosis w/enlargement of the residual airspaces (“honeycomb lung”). (Other choices: It responds well to corticosteroid treatment, The etiology is well understood, It is associated w/an obstructive pulmonary function test pattern.)

Desquamative interstitial pneumonia • Cough, dyspnea, cyanosis, clubbing of fingers. • Macrophages fill alveoli, unknown cause but 90% of patients are smokers. – A lot of the macrophages contain pigment. • Must be differentiated from idiopathic pulmonary fibrosis because DIP may respond to steroids and smoking cessation.

Hypersensitivity pneumonitis • Interstitial granulomas and lymphocytes. o May develop fibrosis over time • Type III immune complex reaction and Type IV delayed hypersensitivity. o Granuloma formation is T-cell mediated and is a type IV reaction • Treatment: End exposure to environmental agent. • Humidifier lung (thermophilic bacteria), pigeon breeder’s lung, farmer’s lung (moldy hay), maple bark stripper’s disease, byssinosis (cotton, hemp fibers). • Different from asthma b/c affects aveoli (allergic alveolitis) Test q: A 29M who presented w/dyspnea has had radiologic and lab eval that has not indicated an etiology for the dyspnea. The decision is made to perform an open lung biopsy and a 3cm wedge of lung tissue is excised. The pathologic diagnosis based on this specimen is hypersensitivity pneumonitis. Which of the following environmental exposures would NOT be likely causative agents? Exposure to freshly ground silica dust. (Other choices: Thermophilic bacteria, Cotton fibers, Antigens from birds, Moldy hay.) Test q: Determination of the etiology of respiratory disease is crucial because of the potential to halt or reverse the damage to the lung by avoidance of etiologic agents. Ending exposure to the agent may be critical to effective treatment. All of the following pulmonary diseases have known environmental agents important in their pathogenesis EXCEPT: Usual-type interstitial pneumonitis (usual-type interstital fibrosis). (Other choices: Desquamative interstitial pneumonitis/fibrosis, Farmer’s lung, Asthma)

Bronchiolitis obliterans-organizing pneumonia (BOOP) • AKA cryptogening organizing pneumonia • Cough, dyspnea. • Response to a variety of inflammatory injuries to the lung: infections, toxins, drugs, rheumatologic disease, graftversus-host disease. • Plugs of fibrous tissue (Masson bodies) in both bronchioles (BO-) and alveoli (-OP). • The connective tissue is all of the same age and underlying lung is normal. No interstitial fibrosis; tx with oral steroids. 1:

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1. Hypersensitivity pneumonitis (farmer’s lung). Interstitium filled w/lymphocytes. Not granuloma here, but could see them in interstitium as well. 2. Bronchiolitis obliterans-organizing pneumonia (BOOP). Masson bodies – Swirly balls/foci of fibroblasts Test q: A 30M presents w/dyspnea and wheezing. No cyanosis is noted. Symptoms have not improved w/treatment w/asthma meds. The patient is a nonsmoker and is a farmer. Pulm function tests show a restrictive pattern and CXR diffuse bilateral haziness of the lungs w/small nodules and lines. A lung biopsy is performed (see below – but no picture is printed on our version of the old test). Which of the following is the most critical next step in the care of this patient: End the patient’s exposure to an environmental agent, possibly moldy hay. (Other choices: Tx w/high dose corticosteroids, Tx w/broad spectrum antibiotics, Complete surgical excision of the lesion seen in the photo, The patient most likely has a pneumoconiosis and, therefore, no treatment will improve his symptoms)

Pulmonary hemorrhage syndrome: • Pulmonary hemorrhage syndrome usually presents with hemoptysis and can be due to Goodpasture’s disease, idiopathic pulmonary hemosiderosis, or Wegener’s granulomatosis • Wegener’s granulomatosis is a vasculitis with granulomas involving the upper and lower respiratory tracts with crescentic glomerulonephritis o Wegeners—granulomas with geographic patterns of central necrosis and accompanying vasculitis • Pathogenesis unknown, probably cell mediated hypersensitivity reaction, responds to immunosupression

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1: Pulmonary hemorrhage in Wegener’s 2: Vasculitis in Wegener’s granulomatosis. Background is necrotic inflammatory debris. Vessel being chewed up by neutrophils in acute vasculitis. Increased PR3-ANCA

Test q: Antineutrophil cytoplasmic antibodies (ANCAs) are antibodies to proteinase-3 and myeloperoxidase that may be observed by immunofluorescence of alcohol-fixed neutrophils. Positive staining may indicate: vasculitis syndromes such as Wegener granulomatosis or microscopic polyangitis. (Other choices: Postinfectious glomerulonephritis, IgA nephropathy/Henoch-Schonlein purpura, Consumption of serum complement factors, Structural disorders of collagen such as Alport syndrome or thin basement membrane disease) Test q: A 44M has developed fever, nonproductive cough, and decreased urine output over the past 3 days. On phys exam, his temp is 37.7C and BP is 145/95. He has sinusitis. On auscultation, crackles are heard over all lung fields. A CXR shows bilateral patchy infiltrates and nodules. The serum creatinine level is 4.1 mg/dL, and the urea nitrogen level is 43 mg/dL. The results of serologic testing are negative for ANA but positive for C-ANCA. A renal biopsy specimen shows glomerular crescents and granulomatous vasculitis. The result of immunofluorescence staining w/anti-IgG and anti-C3 antibodies is negative. Which of the following is the most likely diagnosis? Wegener granulomatosis. (Other choices: Goodpasture syndrome, Lupus nephritis, Membranous glomerulopathy, Postinfectious glomerulonephritis) This was in the kidney section of an old test, but it could be relevant to lung section too ?

Goodpasture’s disease • Goodpasture’s disease: Simultaneous proliferative glomerulonephritis and necrotizing interstitial pneumonia. • Anti-basement membrane autoantibody, seen by immunofluorescence microscopy as linear IgG staining along the basement membrane. o Autoantibody against noncollagenous domain of the alpha-3 chain of collagen 4 • Alveolar wall necrosis and fibrous thickening, organizing blood in alveoli. • HLA-DR2 associated. • ? If triggered by virus/environmental cause, genetic link • Usually present with hemoptysis, renal signs occur after; tx with plasmapheresis Test q: A 50YO high school football coach presents w/complaints of weakness and increasing shortness of breath over the past week. Yesterday he noticed blood in his sputum. On exam, he has a BP of 154/98, bilateral crackles on auscultation of the chest and 2+ ankle edema w/no rash. CXR reveals bilateral infiltrates and serum creatinine is 6.8 mg/dL. You perform a renal biopsy that shows 80% cellular crescents and linear immunofluorescence staining w/anti-IgG along glomerular capillary loops. The clinical presentation and biopsy are most consistent with: Goodpasture’s syndrome. (Other choices: Wegener’s granulomatosis, Heymann’s nephritis, Alport’s syndrome, Berger’s diease) Test q: A 51YO truck driver presents w/complaints of increasing shortness of breath over the past week. Yesterday he began coughing up blood. On exam, he has a BP of 160/100, bilateral crackles on auscultation of the chest and 1+ edema of the lower extremities w/no rashes. CXR reveals bilateral infiltrates and serum creatinine is 7.9 mg/dL. You perform a renal biopsy that shows diffuse crescentic glomerulonephritis with linear immunofluorescent staining of glomerular capillary loops w/anti-IgG antibodies. The clinical presentation and biopsy are most consistent with: Goodpasture’s syndrome. (Other choices: Wegener’s granulomatosis, Heymann’s nephritis, Alport’s syndrome, Berger’s diease)

Neoplastic Lung Pathology: Classification of Lung Tumors • Malignant epithelial neoplasms/Lung carcinomas: – Bronchogenic non-small cell carcinoma  Adenocarcinoma • Variant: Bronchioloalveolar carcinoma  Squamous cell carcinoma • Variant: Basaloid, clear cell  Sarcomatoid carcinoma (pleomorphic, spindle cell, giant cell)  Large cell carcinoma (large cell neuroendocrine, lymphoepithelioma-like)  Adenosquamous – mixture – Bronchogenic small cell carcinoma – Carcinoid tumor (well-differentiated neuroendocrine carcinoma)  Typical/Atypical – Salivary gland-type tumors (mucoep, adenoid cystic, epi/myoep)

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Biphasic epithelial/mesenchymal neoplasms Mesenchymal neoplasms Lymphoproliferative disorders Tumors derived from embryologically displaced or ectopic tissues Tumors of uncertain histogenesis Miscellaneous benign tumors Metastatic tumors involving the lung

 Figure: Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, 2010. Even though breast and prostate cancers are diagnosed more, lung is still the leading cause of cancer death.

1. Annual Age-Adjusted Cancer Death Rates*Among Males for Selected Cancers, United States, 1930 to 2006 2. Annual Age-Adjusted Cancer Death Rates* Among Females for Selected Cancers, United States, 1930 to 2006 Test q: Which of the following curves represents the lung cancer death rate for men? (Did not show pics on our version of the test)

Bronchogenic carcinomas: • 90-95% of all primary lung tumors • Includes the common lung carcinomas – Squamous cell carcinoma (males 32%, females 25%) – Adenocarcinoma (males 37%, females 47%) – Small cell carcinoma (males 14%, females 18%) • Leading cause of cancer death in men and women • Incidence has leveled off in men, may still be increasing in women • Peak incidence between ages 40 and 70 – Most have history of long-term smoking • Only 2% of cases in patients 3 and 7 cm or Invades chest wall, diaphragm, mediastinal pleura, parietal pericardium, within 2 cm of carina, atelectasis/pneumonitis of the entire lung • T4: Invades mediastinum, heart, great vessels, trachea, esophagus, vertebrae, carina, or with malignant pleural effusion • N0: No lymph node metastasis • N1 Metastasis to ipsilateral peribronchial, hilar, or intrapulmonary lymph nodes • N2: Metastasis to ipsilateral mediastinal or subcarinal lymph nodes • N3: Metastasis to scalene, supraclavicular, contralateral mediastinal, or contralateral hilar lymph nodes • M0: No distant metastases • M1: Distant metastases

Prognosis (5-year survival):

As stage increases, survival decreases. Test q: A 60F presents w/a lung mass and a biopsy shows a nonsmall cell carcinoma. With regard to pulmonary nonsmall cell carcinoma, which of the following is the most important prognostic factor? Tumor stage. (Other choices: Tumor grade, Histologic subtype – adenocarcinoma vs. squamous cell carcinoma, Presence or absence of a paraneoplastic syndrome)

Non-small cell carcinoma: • Most bronchogenic non-small cell carcinomas show both glandular and squamous features at both the light microscopic and electron microscopic levels • Cases were commonly diagnosed as non-small cell carcinoma • Old thinking – It is critical to distinguish small cell (chemo) and non-small cell (surgery, if possible, +/- chemo). While there are differences in etiology, gender distribution, and anatomic distribution between pulmonary squamous carcinoma and adenocarcinoma, treatment and prognosis are essentially identical so there is no need to distinguish the two. • Current situation – Adenocarcinomas must be distinguished because they are most likely to have EGFR mutations and therefore be sensitive to tyrosine kinase inhibitors (Iressa, Tarceva) – Angiogenesis inhibitors (Avastin) are used only on adenocarcinoma because a few patients with SCC treated with Avastin have had pulmonary hemorrhage – In reality, some cases of non-small cell carcinoma may have mixed differentiation (adenosquamous carcinoma) or neither glandular or squamous differentiation (non-small cell, NOS). Test q: A patient w/a lung mass undergoes a transbronchial FNA. The aspirates show cohesive (therefore probably epithelial) groups of malignant cells w/marked nuclear enlargement, pleomorphism, and irregularity. Cytoplasm is scant to moderate in volume and no densely keratinized cells, squamous pearls, gland-like formations, or mucin production are seen. The cytopathologist reports the diagnosis as non-small cell carcinoma. The next week, the patient’s oncologist calls the pathologist and asks if the carcinoma is a squamous cell carcinoma or an adenocarcinoma. It is most likely that the oncologist is interested because she is interested in treating the patient with: A tyrosine kinase inhibitor or an angiogenesis inhibitor. (Other choices: Lobectomy, Radiation, Adriamycin, A cephalosporin.)

Molecular findings: • EGFR and KRAS mutations more common in adenocarcinoma. • EGFR mutations more common in women, Asians and non-smokers. • EGFR mutation + show increased survival with EGFR inhibitors • KRAS mutations more common in smokers (30%) than non-smokers (5%). • KRAS mutations associated with worse prognosis and resistance to EGFR inhibitors. • P53, P16, and RB1 mutations/inactivations occur in both squamous and adenocarcinoma. Adenocarcinoma: • Most common type of lung cancer in women and nonsmokers, increasing in incidence • More commonly peripheral • Forms glands, columnar to rounded cells, pale-staining cytoplasm, often with mucin vacuoles • Overall 5-year survival 19%

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1. Pulmonary adenosquamous carcinoma – see difference between glandular area and squamous area. 2. Adenocarcinoma 3. Adenocarcinoma 4:

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4. Pulmonary adenocarcinoma 5. Adenocarcinoma (FNA smears and histology) 6. Adenocarcinoma (FNA smears and histology). Cohesive group of cells, prominent nucleoli = adenocarcinoma 7. Adenocarcinoma (FNA smears and histology) Pattern recognition – cell structure, nucleus location and appearance within cytoplasm, cohesiveness

Bronchioloalveolar carcinoma: • Adenocarcinoma in which the cells grow along the walls of preexisting alveoli • 1-9% of lung carcinomas • Mucinous and non-mucinous subtypes exist • Commonly multiple, peripheral lung masses, may mimic pneumonia clinically and radiologically (patchy pattern), presenting with chough and bronchorrhea • Aerogenous dissemination, satellite nodules are commonly seen • Somewhat better prognosis than bronchogenic carcinoma • 5 year survival ranging from 40 – 90 percent depending on size of tumor  Both figures: Bronchioloalveolar carcinoma See residual lung, tumor cells lining up along alveolar septae – do not penetrate walls. Once it penetrates alveolar walls, it is no longer BAC, it’s adenocarcinoma.

Test q: A 78F has fever, dyspnea, and bilateral, patchy lung infiltrates on CXR. She is hospitalized and treated w/IV antibiotics, but fails to improve. After 1wk, a lung biopsy is performed (see below – but no picture is printed on our version of the old test). The most likely diagnosis is: Bronchioloalveolar carcinoma. (Other choices: Bronchopneumonia, Squamous cell carcinoma, Small cell carcinoma)

Squamous cell carcinoma: • Commonly perihilar, arising in larger bronchi • 98% of cases smoking associated • There may be a progression from squamous metaplasia to squamous dysplasia and then to squamous carcinoma • May be keratinizing (well to moderately-differentiated) with orange, dense cytoplasm, keratin pearls, and intracellular bridges or poorly differentiated • Necrosis is common, may cavitate (and be confused with a cavitary infection such as tuberculosis) • Overall 5-year survival is 15% Test q: A 60M presents w/a lung mass and a biopsy shows squamous cell carcinoma. Assuming you do not have info on tumor stage or other health conditions, what is this patient’s approximate chance of surviving for the next 5yr? 10-20%. (Other choices: Less than 10%, 30-50%, More than 50%) Test q: A 72M presents w/cough and mild dyspnea. The patient has a 100 pack-year smoking history. Right cervical lymphadenopathy is noted. He has some sputum production and cytologic exam is requested. The patient has malignant cells on cytology. A CXR shows a right apical lung mass w/central necrosis. A biopsy is performed (see below – but no picture is printed on our version of the old test). The diagnosis is: Squamous cell carincoma. (Other choices: Adenocarcinoma, Small cell carcinoma, Carcinoid tumor) Test q: A 49M has sudden onset of severe lower abdominal pain w/hematuria. He passes a ureteral calculus. Lab studies show that the calculus is composed of calcium oxalate. He is found to have a serum calcium concentration of 10.2 mg/dL, serum phosphorus level of 2.9 mg/dL, and serum albumin level of 4.6 g/dL. A CXR shows a 7cm hilar mass in the right lung. A chest CT scan shows prominent central necrosis in this mass. Which of the following neoplasms is most likely to be associated w/these findings? Squamous cell carcinoma. (Other choices: Metastatic colonic adenocarcinoma, Small cell carcinoma, Bronchioloalveolar carcinoma, Primary pulmonary adenocarcinoma)

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1. SCC with keratin pearls 2. SCC with tumor extending into bronchus. Left side of pic: tumor. Right: hard to interpret. Can see respiratory lining in the middle. Can see keratin pearl formation. Pink-orangish squamous cytoplasm. 3. Squamous cell carcinoma obstructing bronchus. Test q: A 58M presents w/a recent history of a 20lb unintended weight loss, increasing cough, and sputum production. Chest CT shows a 3.5cm right hilar lung mass, but no hilar or mediastinal lymphadenopathy. Bronchoscopy w/bronchial washing cytology and transbronchial FNA is performed. Both studies are positive for malignant cells. The patient has a pulmonary lobectomy, and a section from this specimen is shown . Which of the following is true about this tumor? Central necrosis is common which may give the radiographic impression of a cavitary lesion. (Other choices: 5yr survival is better than that for head and neck squamous cell carcinomas, Peripheral lung location is more common than the hilar location seen in this case, This is the type of lung tumor which is most likely to spread by aerogenous dissemination, This tumor cannot be diagnosed by sputum cytology.)

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1. Squamous cell carcinoma on a FNA smear. Atypical keratinized cells – orange. 2. Bronchial squamous metaplasia with severe squamous dysplasia. Used to be respiratory epithelial lining, became squamous (severe squamous dysplasia)  tumor is likely nearby. 3. Sarcomatoid change in a squamous cell carcinoma. See spindle atypical cells (bottom arrow), mitotic figures (top arrow). Small cell carcinoma: • Commonly central, mediastinal involvement common at presentation, 99% associated with smoking • Regarded as a systemic disease (treated with chemotherapy, not surgery) as nearly all patients have lymph node and distant metastases at presentation • Very aggressive, median survival only 10-16 months in patients with low stage disease with treatment • Composed of moderate sized nuclei with very scant cytoplasm, finely granular chromatin, inconspicuous nucleoli o Will see molding – grow around one another. • May at times be difficult to distinguish from poorly differentiated non-small cell carcinoma, neuroendocrine immunohistochemical stains (chromogranin and synaptophysin) may be useful to confirm the diagnosis • Paraneoplastic: SIADH, Lambert-Eaton (proximal muscle weakness) 4:

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4. Small cell carcinoma in a transbronchial biopsy. See moderatelysized nuclei w/very scant cytoplasm. Form cords of tumor cells. Can see molding of cells. 5. Small cell carcinoma with nuclear molding on FNA smear. Arrow = Molding (see flat sides)

Test q: A 60M presents w/cough and hemoptysis. On CT-scan of the thorax, there is a 4cm right hilar lung mass and bilateral mediastinal lymphadenopathy. A pulmonologist performs bronchoscopy and a transbronchial fine needle aspiration. The smears show abundant poorly differentiated tumor cells w/very scant cytoplasm and a cell block is prepared. Which of the following immunohistochemical and mucicarmine staining patterns would be most supportive of a diagnosis of small cell carcinoma? Keratin +, synaptophysin+, CD45-, mucin-. (Other choices: keratin/synaptophysin-/CD45-/mucin-; keratin-/synaptophysin-/CD45+/mucin-; keratin+/synaptophysin-/CD45-/mucin+) Test q: Assuming the dx of small cell carcinoma for the patient in the question above is confirmed, which of the following is true? The patient is almost certainly a smoker (99-100% likelihood). (Other choices: The patient is a surgical candidate, PTH-related peptide associated w/hypercalcemia is the most likely paraneoplastic syndrome, The 5-year survivaly rate is approx 50%) Test q: A 39F has a 6cm well-circumscribed solid anterior mediastinal mass. The mass does not invade the lungs, esophagus, or heart. A core needle biopsy is performed w/CT guidance. The biopsy shows small nests of cells w/moderately enlarged nuclei and scant cytoplasm in a background of abundant lymphocytes. No cystic areas or evidence of squamous or glandular differentiation is seen. Immunohistochemical stains are performed and the nests of cells are positive for keratin and the background lymphocytes are positive for CD3. Which of the following is true? The patient is likely to have a history of episodes of muscle weakness. (Other choices: As the nests of cells are positive for keratin, the dx is metastatic squamous cell carcinoma in a lymph node. The positive CD3 stain indicates that this is a B-cell lymphoma. The tumor is probably a mature teratoma. The mass is probably an enlarged – but benign – lymph node.)

Carcinoid tumor: • Bronchial carcinoids 1-5% of lung tumors • World Health Organization classifies it as grade 1 (well-differentiated) neuroendocrine carcinoma • Polypoid, submucosal, circumscribed mass, may cause bronchial obstruction • Cells with round, relatively uniform nuclei, coarse chromatin, and moderately abundant cytoplasmic granules • Architecture may be nested, trabecular, or solid • Neuroendocrine immunohistochemical stains (chromogranin and synaptophysin) may be useful to confirm the diagnosis • Greater than 90% 5-year survival with surgery for typical carcinoids Test q: A 52M has lung biopsy performed. Which of the following diagnoses is associated with the best 5yr survival? Carcinoid tumor. (Other choices: Bronchioloalveolar carcinoma, Small cell carcinoma, Squamous cell carcinoma, Usual type interstitial pneumonia/fibrosis)

 Carcinoid tumor (both pics): Salt-and-pepper chromatin, monotonous nuclei – same size, shape, smooth borders, decent amount of cytoplasm, nucleus pushed off to the side (plasmacytoid appearance).

Test q: A 53M presents w/recurrent pneumonia and, on bronchoscopy, has a well-circumscribed 1cm submucosal endobronchial mass. Biopsy is performed and shows cells w/small, round nuclei w/stippled (“salt and pepper”) chromatin arranged in a trabecular pattern. Cytoplasm is moderately abundant and granular at high power. Which of the following histochemical and immunohistochemical staining patterns would be most supportive of the diagnosis of carcinoid tumor? Mucin -, keratin +, synaptophysin +, chromogranin +. (Other choices: Mucin+/keratin+/synaptophysin-/chromogranin, Mucin+/keratin+/synaptophysin-/chromogranin+, Mucin-/keratin-/synaptophysin-/chromogranin-.) Test q: A 48F has recurrent right middle lobe pneumonia. A CXR shows a possible mass and bronchoscopy is performed. Bronchoscopy shows a mass protruding into the bronchus and a biopsy is performed and placed in formalin for histology (see below – but no picture is printed on our version of the old test). A histochemical stain for mucin is negative and an immunohistochemical stain for keratin is positive. Which of the following is true? Immunohistochemical stains for chromogranin and synaptophysin will probably be positive. (Other choices: The positive keratin stain indicates that it is a squamous cell carinoma, Special stains for acid-fast bacteria and fungi should be performed, The specimen should have been submitted for culture and not histology since the patient had clinical evidence of pneumonia.) Don’t know what type of mass they’re talking about since no pic was printed with it. Could be small cell carcinoma or carcinoid tumor based on the immunohistochemistry. “Protruding into the bronchus” may be a clue pointing towards carcinoid, however, since the notes say “may cause bronchial obstruction.”

Mesothelioma: • Associated with asbestos, especially amphibole asbestos, exposure • 3:1 male:female ratio • Lifetime risk of mesothelioma in the heavily exposed is 7-10% • May be sarcomatoid (20%), epithelioid (60%), or mixed (20%) • Poor prognosis, few patients survive longer than 2 years Pulmonary hamartoma: • Benign tumor, may be recognized radiologically so not commonly biopsied • Composed of cartilage and other disorganized benign soft tissue such as fat, smooth muscle, bone, may also contain bone marrow • 1:

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1. Epithelioid mesothelioma – cuboidal, columnar, or flattened cells forming tubular or papillary structures resembling adenocarcinoma (so do stains to support dx) 2. Sarcomatoid mesothelioma – fibrosarc oma Can be mixed. 3. Pulmonary hamartoma

Test q: A 40F presents w/a cough and fever and has a CXR, which demonstrates a 1.5cm solid mass near a large bronchus. In order to rule out malignancy, a transbronchial FNA is attempted, but is hypocellular and, therefore, nondiagnostic. The decision is made to excise the nodule. Gross exam shows a well-defined bluish-white somewhat translucent nodule. A histologic section is shown . The best diagnosis is: Pulmonary hamartoma. (Other choices: Carcinoid tumor, Granulomatous inflammation, Pulmonary embolus, Chondrosarcoma.) Test q: A 73M presents w/shortness of breath and, on radiographic evaluation of the chest, is found to have a large unilateral pleural effusion and a mass encasing the right lung. Thorocentesis is performed and the fluid is highly cellular, but a mucin stain is negative. Tumor radiographically diffusely involves the pleura and tumor nodules are not seen within the lung parenchyma. A biopsy of the mass is shown . What historical info would be most helpful in establishing the diagnosis in this case? A history of asbestos exposure. (Other choices: Smoking history, Beryllium exposure history, Travel history – particularly travel to a malaria-endemic area, History of exposure to birds or moldy hay.)

Sclerosing hemangioma: • AKA sclerosing pneumocytoma • Rare benign lung tumor, usually asymptomatic well-circumscribed mass • Poor name, the tumor cells are probably type II pneumocytes • Papillary and gland-like groups surrounding fibrovascular cores Primary tumors of the mediastinum: • Thymoma • Germ cell tumors • Lymphoma • Thymic and other benign cysts • Lesions of ectopic thyroid or parathyroid • Mesenchymal tumors (benign and sarcomas) Thymoma: • Normal thymus is a mixture of epithelial cells and lymphocytes (T-cells) • Thymomas are epithelial tumors, but may have admixed lymphocytes, sometimes so much so that the epithelial component is difficult to recognize • As epithelial tumors, diagnostic techniques specific for lymphomas (flow cytometry) will not be helpful in diagnosis 1:

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3: 1. Sclerosing hemangioma 2. Normal thymus 3. Thymoma

Thymoma: Lots of lymphocytes – very small, scant cytoplasm. See abnormal neoplastic epithelial cells. Thymoma presentation: • Anterior mediastinal mass • One third to one half of patients will have paraneoplastic myasthenia gravis (variable muscle weakness due to an acetylcholine receptor autoantibody) • May histologically have round or spindle shaped cells, may have glands, usually has associated lymphocytes • Prognosis good, unless evidence of local invasion exists (in which case the tumor may be considered a thymic carcinoma)

Head and Neck Pathology Malignancies of the upper aerodigestive tract: • Approximately 3.5% of U.S. cancer cases • Squamous cell carcinoma represents 95% of head and neck cancers • May present with ulcerated mucosa, hoarseness, odynophagia, dysphagia, dentalgia, otalgia, otitis media, pain radiating to the ear, cervical lymphadenopathy Etiology of SCC: • SCC is usually associated with smoking and/or alcohol use • Smokeless tobacco • HPV may also be detected in 50% or more of head and neck SCCs • Sun exposure for SCC of lip Test q: A 54M, non-smoker, has a non-healing ulceration at the right base of his tongue for 2mo. On exam, this lesion is 1cm in diameter w/irregular borders. Biopsy of the lesion is performed and micro exam shows infiltrating squamous cell carcinoma. Which of the following infectious agents is most likely to be associated w/this lesion? HPV. (Other choices: Candida albicans, Herpes simplex virus, Prevotella intermedia, Streptococcus Group A.) Test q: What risk factor is important for squamous cell carcinoma of the lip, but not for squamous cell carcinoma of the oral cavity and oropharynx? Sun exposure. (Other choices: Alcohol, smoking, smokeless tobacco)

Premalignant lesions: • Leukoplakia – A clinical term for a white patch of oral mucosa (not a pathologic diagnosis), 5-25% of these are precancerous (dysplastic) • Erythroplasia – A clinical term for a red patch of oral mucosa (also not a pathologic diagnosis), more ominous, 90% of these are precancerous (dysplastic) • Oral mucosal dysplasia is thought to progress through mild squamous dysplasia, moderate squamous dysplasia, and severe squamous dysplasia/carcinoma in situ stages with accumulation of genetic alterations prior to invading – Inactivation of the p16 cyclin-dependent kinase gene – Mutation of the p53 tumor suppressor gene – Overexpression of cyclin D1 (a cell cycle regulator) Test q: Which of the following clinical findings is most likely to be associated w/malignancy on exam of the oral cavity? Erythroplasia. (Other choices: Thrush, leukoplakia, xerostomia) Test q: Which of the following is true concerning squamous cell carcinoma of the head and neck? Erythroplasia is more likely than leukoplakia to be associated w/carcinoma. (Other choices: Systemic metastases are common at presentation, even in the absence of ipsilateral cervical lymph node metastases. Chemotherapy alone is usually curative. Death is usually due to metastatic disease, not locoregional progression.)

Squamous cell carcinoma presenting as cervical lymphadenopathy: • FNA is the usual method for sampling a suspicious cervical lymph node in an adult • Random biopsies of nasopharynx, tongue, tonsil, hypopharynx may sometimes be done if SCC is identified in a lymph node and no mucosal lesion is seen • In this situation, tonsillectomy ipsilateral to the lymph node may detect the primary tumor in 18% of cases Test q: A 60M presents w/a 2cm right cervical lymph node. The patient was previously treated w/antibiotics for 2wk without a decrease in size of the lymph node. The patient does not report hoarseness or any recent upper resp tract infections. The patient drinks alcohol occasionally and smokes approx.10 cigs/day. The appropriate next step in the management of this patient is: Fine needle aspiration biopsy of the lymph node. (Other choices: Right cervical lymph node dissection, PET scan, External beam radiation therapy to the lymph node) Test q: Which of the following is a common site of origin for metastatic squamous cell carcinoma in a cervical lymph node w/an occult primary site? Tonsil. (Other choices: Lip, eyelid, parotid gland) Test q: Systemic metastases are uncommon at presentation w/squamous cell carcinoma of the head and neck. When metastases beyond the cervical lymph nodes are seen, what are the most common sites? Lung and bone. (Other choices: Brain and liver, kidney and adrenal, inguinal and pelvic lymph nodes) Not mentioned in class?

Sites of involvement: • Oral cavity – May involve hard palate, buccal mucosa, alveolar ridges, floor of mouth, tongue, retromolar trigone – May develop from previously recognized erythroplakia or leukoplakia – Metastasizes to level I and II lymph nodes

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Lip – 12% of noncutaneous head and neck cancers – Best prognosis for head and neck noncutaneous SCC – Related to sun exposure Oropharynx – Tumors large at presentation – Metastases to level II and III lymph nodes Larynx – Most common site for head and neck cancer Hypopharynx – Level III and IV lymph node metastases Nasopharynx – May be undifferentiated, especially in Asian patients – Treated with radiation due to difficulty of surgical resection Paranasal sinus – Rare, most commonly in maxillary sinus – Proptosis, facial swelling, symptoms of sinusitis 2:

1. Prognosis by site (5-year survival). Of the head/neck sites, SCC of the lip has best prognosis. SCC of the hypopharynx has the worst prognosis. However, lung squamous cell carcinoma has the worst rate, with overall survival of 15%. 2. SCC of the lip Test q: The prognosis of squamous cell carcinoma is worst at which of the following sites? Lung. (Other choices: Lip, hypopharynx, Tonsil, Tongue) Test q: A 68M presents w/hoarseness and on clinical eval, a 2cm mass involving the larynx is detected. A biopsy is performed. The slides show a tumor composed of oval to spindle-shaped nuclei in a background of fibrous tissue. The nuclei are markedly pleomorphic and enlarged and frequent mitoses are seen. An immunohistochemical stain for keratin is performed and is positive. The currently accepted explanation for this situation is: The tumor is a carcinoma which is so poorly differentiated that it no longer microscopically resembles epithelium. (Other choices: The tumor is a sarcoma which has developed expression of keratin intermediate filaments, The biopsy sampled the desmoplastic response adjacent to the tumor, The tumor is a pleomorphic adenoma, The tumor is a poorly-differentiated chondrosarcoma arising in the laryngeal cartilage.)

Nasopharyngeal carcinoma: • Unusual age and geographic distribution, more common in children in Africa, adults in southern China, rare in U.S. • May cause unilateral obstruction of the Eustachian tube with resulting unilateral otitis media • EBV identified in malignant epithelial cells • May be undifferentiated or keratinizing • Treated with radiation, the undifferentiated form is especially radiosensitive Test q: A 65y/o Asian American man presents with intermittent ear pain of 4wks duration. Exam w/an otoscope demonstrates fluid behind the tympanic membrane. This clinical presentation should raise specific concern for which of the following? Undifferentiated nasopharyngeal carcinoma (Other choices: Nasopharyngeal angiofibroma, Nasofacial NK/T-cell lymphoma, Warthin’s tumor) Test q: For the past 4mo, a 50M has had difficulty breathing through his nose and has also experienced dull facial pain. On phys exam, there is a mass filing the right nasal cavity. CT scan of the head shows a 4cm mass in the nasopharynx on the right that erodes the adjacent bone. The mass is excised and microscopic exam shows that it is composed of large epithelial cells w/indistinct borders and prominent nuclei. Mature lymphocytes are scattered throughout the undifferentiated neoplasm. Which of the following etiologic factors most likely played the greatest role in the development of this lesion? Epstein-Barr virus infection. (Other choices: Sjogren syndrome, Smoking tobacco, Allergic rhinitis, Wegener granulomatosis) REPEATED x2 Test q: Undifferentiated nasopharyngeal carcinoma is associated with exposure to which virus? EBV. (Other choices: HCV, HTLV-1, CMV)

Salivary gland tumors: • Pleomorphic adenoma • Carcinoma ex pleomorphic adenoma • Warthin’s tumor • Mucoepidermoid carcinoma • Acinic cell carcinoma • Adenoid cystic carcinoma Pleomorphic adenoma (benign mixed tumor): • Most common salivary gland tumor (comprising approximately 60% of tumors) • Grossly gelatinous or cartilage-like, blue-white in color • Composed of two components, gland/duct-like structures and myxoid stroma, thought to differentiate from myoepithelial cells • Benign, but may rarely progress to carcinoma (carcinoma ex pleomorphic adenoma). The typical history is recent rapid growth in a parotid mass that has been present for many years. 2:

3: 1. Normal parotid gland 2. Pleomorphic adenoma: PA epithelial (and stromal) component 3. Pleomorphic adenoma: PA myxoid stromal component

Test q: The cells of pleomorphic adenoma may stain with immunohistochemical statins for vimentin, S-100 protein, desmin, actin, and epithelial membrane antigen. These findings support the concept that pleomorphic adenomas are neoplasms that show differentiation toward what cell type? Myoepithelial. (Other choices: Neuroendocrine, Endothelial, Melanocytic) Test q: A 74M presents w/painless swelling of the left cheek. Exam reveals a 3cm, firm, nontender, well-defined nodule in the soft tissue of the parotid region. The nodule is excised. Gross exam shows a firm, bluish-white translucent tumor. A photo of a histologic section is shown . The diagnosis is: Pleomorphic adenoma. (Other choices: Acinic cell carcinoma, Sq cell carcinoma, NonHodgkin lymphoma, Adenoid cystic carcinoma)

Warthin’s tumor (papillary cystadenoma lymphomatosum): • Second most common benign tumor of the parotid • Most common bilateral parotid tumor • Benign, associated with smoking • Oncocytic epithelium covering papillary structures with a dense lymphoid stroma

All 3 figures above: Warthin’s tumor. Oncocytic cells lining cystic spaces, lymphocytes. Test q: A 56M notices a lump on the right side of his face that has become larger over the past year. On phys exam, a 3-4cm firm, mobile, painless mass is palpable in the region of the right parotid gland. The oral mucosa appears normal. He does not complain of difficulty in chewing food or talking. The mass is completely excised and histologic exam shows spaces lined by a double layer of superficial columnar and basal cuboidal epithelial cells that are surrounding a lymphoid stroma. The epithelial cells have abundant eosinophilic cytoplasm. What is the most likely diagnosis? Warthin’s tumor. (Other choices: Mucoepidermoid carcinoma, Non-Hodgkin lymphoma, Pleomorphic adenoma, Sialolithiasis)

Test q: A 75M has had a subcutaneous nodule near the angle of the mandible for approximately 1yr. The patient is a smoker and has smoked approx 1 pack/day for 50yr. On exam, the nodule is well-circumscribed, soft, and about 1.5cm in diameter. A FNA is recommended because of concern for metastatic malignancy, especially in light of this patient’s smoking history. The patient, however, declines a FNA as he would like to have the nodule removed and the nodule is surgically excised. A histologic section is shown . The diagnosis is: Warthin’s tumor. (Other choices: Squamous cell carcinoma, HIV-assoc’d lymphoepithelial cyst, Pleomorphic adenoma, Non-Hodgkin lymphoma of the MALT type)

Mucoepidermoid carcinoma: • Malignant tumor composed of squamous cells, mucin-producing cells, and intermediate cells • Most common minor salivary gland tumor o Also – Most common primary malignant tumor of the salivary gland Test q: Which of the following are the cellular components of a mucoepidermoid carcinoma? Mucus-secreting, intermediate, squamous. (Other choices: Smooth muscle/ductal/acinar. Goblet cell/melanocytic/histiocytic. Squamous cell/acinar cell/transitional cell.)

Acinic cell carcinoma: • Malignant epithelial neoplasm that demonstrates differentiation towards acinar cells • 90% involve the parotid • Cells have abundant eosinophilic granular cytoplasm, generally round nuclei Adenoid cystic carcinoma: • Slow growing tumor • Perineural invasion is characteristic o Tricky to resect b/c of perineural invasion…5 year survival OK (60-70%) but 10 year is 30% due to the high probability of recurrence and distant mets • Very characteristic histology with cribriform pattern with basement membrane-like hyaline material within the lumens 1:

2:

3:

1. Mucoepidermoid carcinoma 2. Acinic cell carcinoma: No lymphocytes like in Warthin’s. Cytoplasm is more granular. 3. Adenoid cystic carcinoma: See big chunk of nerve, tumor wrapping around, hard to follow surgically.

Test q: A 45F presents w/right facial pain and swelling. Phys exam reveals a 2cm firm parotid region mass. A FNA is performed and is reported as “Malignant cells are present from a poorly differentiated epithelial neoplasm”. A parotidectomy is performed and a histologic section is shown . The best dx is: Adenoid cystic carcinoma. (Other choices: Pleomorphic adenoma, Warthin’s tumor, Sq cell carcinoma, Metastatic melanoma)

Other tumors of the head and neck: • Sinonasal papilloma • Nasal angiofibroma • Nasopharyngeal carcinoma • Soft tissue tumors • Thyroid/parathyroid tumors (discussed in endocrine pathology) • Lymphoma  Schwannoma

Sinonasal papilloma: • Benign neoplasms with squamous and columnar epithelium, edematous stroma • Inverted papilloma subtype may have locally aggressive behavior o High rate of recurrence secondary to inadequate resection o Papillary features dig into underlying connective tissue Nasal angiofibroma: • Young patients • Recurrent epistaxis, unilateral nasal obstruction on exam • Angiography shows hypervascular mass fed by internal maxillary artery • May have severe bleeding if biopsied Test q: A 13M presents w/unilateral nasal obstruction and a history of epistaxis on the same side. A nasal cavity mass is seen on MRI and angiography is subsequently performed showing a highly vascular lesion w/blood supply from the internal maxillary artery. The mass is resected (see below – but no picture is printed on our version of the old test). The diagnosis is: Nasopharyngeal angiofibroma. (Other choices: Olfactory neuroblastoma – esthesioneuroblastoma, Squamous cell carcinoma, Non-Hodgkin lymphoma) Test q: A 15M presents w/recurrent epistaxis. On exam, there is unilateral nasal obstruction by a tumor. Angiography demonstrates a hypervascular mass which is fed by a branch of the interal maxillary artery. Biopsy should be performed with caution due to the possibility of which of the following tumors? Juvenile angiofibroma. (Other choices: Inverted papilloma, Nasopharyngeal carcinoma, Olfactory neuroblastoma)

Head and neck lymphomas: • A variety of lymphoma types may be seen including diffuse large B-cell lymphoma, MALT-type lymphomas, nasofacial T-cell lymphoma (which has an especially poor prognosis) • HIV is a risk factor and high grade lymphomas predominate in HIV patients Test q: A 40F has been HIV+ for 10yr and develops a head and neck region lymphoma. Which of the following are true statements about non-Hodgkin lymphoma in the setting of HIV infection (versus HIV negative patients)? The lymphoma is more likely to involve the CNS and is more likely to be high grade. (Other choices: Most lymphomas in HIV+ patients are Burkitt or lymphoblastic types, Long term – 5yr survival – after the diagnosis of lymphoma is higher for HIV-infected patients, Nasofacial NK/T-cell lymphoma and MALT lymphoma are unique to HIV-infected patients) Test q: Which of the following statements is true concerning lymphoma of the head and neck? High grade lymphomas predominate in HIV+ patients. (Other choices: Almost all head and neck lymphomas involve lymph nodes before progressing to involve other sites, Head and neck lymphomas are all derived from B-lymphocytes, Extranodal marginal zone B-cell lymphomas are the most aggressive clinically)

1:

2:

3: 1. Sinonasal papilloma 2. Nasal angiofibroma 3. MALT lymphoma of adenoids

Extranodal NK/T-cell lymphoma, nasal type (Nasofacial T-cell lymphoma): • Previously called “lethal midline granuloma” • T-cell lymphoma with destruction of nose and palate • Expresses CD2 (a T-cell marker) and other T-cell and NK cell related antigens • Very aggressive with survival often measured in months Tumors and cysts of the jaws: • A wide variety of tumors and cysts arise in the jaws – One example is ameloblastoma, a slow growing locally invasive but generally benign tumor arising from odontogenic epithelium Ameloblastoma of the mandible 

Leftover test questions: Test q: A 45M presents w/cough w/sputum production of 6mo duration. He reports dyspnea w/exercise and states that occasionally, gelatinous material is present in his sputum. A lung biopsy is performed (see below – but no picture is printed on our version of the old test). This patient’s disease may be related to an autoantibody specific for which of the following? GM-CSF. (Other choices: Surfactant protein B, Angiotensin converting enzyme, Heat shock protein 60). Test q: A 6wk old male infant, born at 40wk estimated gestational age, has a fever and mild resp symptoms. After several days, the fever fails to improve and a CXR is performed. A 1cm right apical lung mass is described by the radiologist. The mass is excised (see below – but no picture is printed on our version of the old test), with a rim of surrounding normal lung tissue. The most likely diagnosis is: Bronchopulmonary sequestration (Other choices: Bronchogenic cyst – foregut cyst, Hyaline membrane disease, Pulm alveolar proteinosis) Test q: A 17F is concerned about a “bump” on her neck that she has noticed for several months. It does not seem to have increased in size appreciably during that time. On phys exam, there is a discrete, slightly movable nodule in the midline of the neck just above the thyroid gland. The nodule is excised, and micro exam shows a cystic mass lined by squamous and respiratory epithelium. Which of the following additional histologic elements would most likely be located adjacent to this cyst? Thyroid. (Other choices: Malignant lymphoma, Serous salivary glands, Noncaseating granulomas) Robbins explanation: The location of this nodule is classic for a thyroglossal duct (tract) cyst, which is a developmental abnormality that arises from elements of the embryonic thyroglossal duct extending from the foramen cecum of the tongues down to the thyroid gland. One or more remnants of this tract may enlarge to produce a cystic mass. Test q: Which of the following is true concerning tumor-like masses of the head and neck in children? The majority are benign. (Other choices: Midline masses are usually branchial cleft cysts, Neuroblastoma is the most common cause of cervical lymphadenopathy, Squamous cell carcinoma is the most common malignant salivary gland tumor.) Test q: A 44F has recurrent right maxillary sinusitis. Endoscopic exam of the nasal cavities reveals obstruction in the right nasal cavity by polypoid, edematous appearing mucosa. A biopsy is performed (see below – but no picture is printed on our version of the old test). The most likely diagnosis is: Nasal polyps. (Other choices: Squamous cell carcinoma, Angiofibroma, Angiocentric NK/T-cell lymphoma) Test q: In patients w/malignancies of the head and neck, diplopia may result from involvement of which of the following sites? Cavernous sinus. (Other choices: Base of skull, Parotid region, Eustachian tube)