Respiratory Pathology Spring 2025 PDF

Respiratory pathology Dr. Danny Mora Oral and Maxillofacial Pathologist Dr. Danny Mora Oral and Maxillofacial Pathologist Disclosure: Most photos are from Copyright © 2017, by Elsevier Inc. All rights reserved. Dr. Danny Mora Oral and Maxillofac...

Respiratory pathology Dr. Danny Mora Oral and Maxillofacial Pathologist Dr. Danny Mora Oral and Maxillofacial Pathologist Disclosure: Most photos are from Copyright © 2017, by Elsevier Inc. All rights reserved. Dr. Danny Mora Oral and Maxillofacial Pathologist  The student will know the different types diseases and tumors that develop in the Objectives lungs Will be able to recognize microscopically the most common types Dr. Danny Mora Oral and Maxillofacial Pathologist  TheLungs Their function is the exchange of gases between inspired air and blood. The right main stem bronchus is more vertical and more directly in line with the trachea. Consequently, aspirated foreign materials, such as vomitus, blood, and foreign bodies, tend to enter the right lung more than the left. Dr. Danny Mora Oral and Maxillofacial Pathologist Alveoli Trachea and bronchi Dr. Danny Mora Oral and Maxillofacial Pathologist  NormalLungtissue Except for the vocal cords, which are covered by stratified squamous epithelium, the entire respiratory tree, including the larynx, trachea, and bronchioles, is lined by pseudostratified, tall, columnar, ciliated epithelial cells. The bronchial mucosa also contains a population of neuroendocrine cells that have neurosecretory-type granules and can release serotonin, calcitonin, and gastrin-releasing peptide (bombesin). Numerous mucus-secreting goblet cells and submucosal glands are dispersed throughout the walls of the trachea and bronchi (but not the bronchioles). Dr. Danny Mora Oral and Maxillofacial Pathologist  Alveoli Dr. Danny Mora Oral and Maxillofacial Pathologist Pulmonaryedema Dr. Danny Mora Oral and Maxillofacial Pathologist  PULMONARY EDEMA Pulmonary edema is a condition caused by excess fluid in the lungs. Hemodynamic Pulmonary Edema Increased hydrostatic pressure, seen in left-sided congestive heart failure. Alveolar capillaries are congested and there is an intra- alveolar granular pink precipitate. Alveolar micro hemorrhages and hemosiderin-laden macrophages. Edema Caused by Microvascular Injury The pulmonary capillary hydrostatic pressure is not elevated, and hemodynamic factors play a secondary role. The edema results from primary injury to the vascular endothelium or damage to alveolar epithelial cells (with secondary microvascular injury). This results in leakage of fluids and proteins first into the interstitial space and, in more severe cases, into the alveoli. Dr. Danny Mora Oral and Maxillofacial Pathologist  Acute LungInjuryand Acute RespiratoryDistressSyndrome (DiffuseAlveolar Damage) Acute lung injury (ALI) (noncardiogenic pulmonary edema) is characterized by the abrupt onset of significant hypoxemia and diffuse pulmonary infiltrates in the absence of cardiac failure. Acute respiratory distress syndrome (ARDS) refers to severe ALI. ARDS and ALI both increase in pulmonary vascular permeability, and epithelial and endothelial cell death. The histologic manifestation of these diseases is diffuse alveolar damage (DAD). Most cases of ALI are associated with an underlying etiology such as sepsis. Dr. Danny Mora Oral and Maxillofacial Pathologist  Acute LungInjury In the acute stage, the lungs are heavy, firm, red, and boggy. They exhibit congestion, interstitial and intra- alveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage. The alveolar walls become lined with waxy hyaline membranes that are morphologically similar to those seen in hyaline membrane disease of neonates. In the organizing stage, type IIpneumocytes undergo proliferation, and there is a granulation tissue response in the alveolar walls and in the alveolar spaces. Fatal cases often have superimposed bronchopneumonia. Dr. Danny Mora Oral and Maxillofacial Pathologist  Pathogenesis The acute consequences of damage to the alveolar capillary membrane include: – Increased vascular permeability – Alveolar flooding – Loss of diffusion capacity – Widespread surfactant abnormalities caused by damage to type IIpneumocytes. Endothelial injury also triggers the formation of micro thrombi that add the insult of ischemic injury. Hyaline membranes result from inspissation of protein rich edema fluid that entraps debris of dead alveolar epithelial cells. Dr. Danny Mora Oral and Maxillofacial Pathologist Clinical Course Profound dyspnea and tachypnea Increasing cyanosis and hypoxemia Respiratory failure Early in the course of the disease, lungs become stiff due to loss of functional surfactant. Due to improvements in therapy for sepsis, mechanical ventilation, and supportive care, the mortality rate has decreased from 60% to about 40%. The majority of deaths are attributable to sepsis or multi-organ failure and, in some cases, direct lung injury. Dr. Danny Mora Oral and Maxillofacial Pathologist  Obstructive versus RestrictivePulmonary Diseases Obstructive diseases, is an increase in resistance to airflow due to partial or complete obstruction at any level. Restrictive diseases, characterized by reduced expansion of lung parenchyma and decreased total lung capacity. – Restrictive defects occur in two general conditions: Chest wall disorders (e.g., neuromuscular diseases such as poliomyelitis or muscular dystrophy, severe obesity, pleural diseases, and kyphoscoliosis) Chronic interstitial and infiltrative diseases, such as pneumoconioses and interstitial fibrosis of unknown etiology. Dr. Danny Mora Oral and Maxillofacial Pathologist  Obstructive Pulmonary Disease Asthma Emphysema Chronic Bronchitis Bronchiectasis Bronchiolitis Obliterans Dr. Danny Mora Oral and Maxillofacial Pathologist  Emphysema Is defined as abnormal, permanent enlargement of air spaces distal to the terminal bronchioles, due to destruction of alveolar walls without fibrosis. COPD is a major public health problem. It is the fourth leading cause of morbidity and mortality in the United States and is projected to rank fifth by 2020 as a worldwide burden of disease. There is a proven association between heavy cigarette smoking and emphysema, and women and African Americans are more susceptible than other groups. Dr. Danny Mora Oral and Maxillofacial Pathologist  Emphysema ⦿ It is classified as follows: ⚫ Centriacinar emphysema ○ Involves primarily the respiratory bronchioles ○ Most common type. ○ Seen in cigarette smokers. ⚫ Panacinar emphysema ○ Involves the entire acinus. ○ It is one-twentieth as common as centricular emphysema. ○ Seen in alpha 1 - antitrypsin deficiency. Dr. Danny Mora Oral and Maxillofacial Pathologist  Emphysema – Paraseptal emphysema Involves the distal part of the lobule. Extensive involvement of the lung is rare. Irregular emphysema Is associated with scarring and has no particular relationship to the acinus. – Bullous emphysema Composed of lesions (bulla) greater than 1 cm. in diameter, and can be associated with any type of emphysema. Dr. Danny Mora Oral and Maxillofacial Pathologist  Emphysema Macrophages, CD8+ and CD4+ T lymphocytes, and neutrophils are increased. Activated inflammatory cells release a variety of mediators, including leukotriene B4, IL-8, TNF, and others, that are capable of damaging lung structures or sustaining neutrophilic inflammation. Centriacinar and panacinar thought to be secondary to the destruction of alveolar walls by the imbalance of oxidants and antioxidants. Dr. Danny Mora Oral and Maxillofacial Pathologist  Clinical Manifestations The clinical manifestations of emphysema appear until at least one third of the functioning pulmonary parenchyma is damaged. Dyspnea is usually the first symptom; Cough Weight loss is common and can be so severe as to suggest a hidden malignant tumor. Expiratory airflow limitation. Development of cor pulmonale and eventually congestive heart failure, related to secondary pulmonary vascular hypertension, is associated with a poor prognosis. Death in most patients with emphysema is due to – Respiratory acidosis and coma, – Right-sided heart failure, – Massive collapse of the lungs secondary to pneumothorax. Treatment – Bronchodilators, steroids, bullectomy, and, in selected patients, lung volume reduction surgery and lung transplantation. Dr. Danny Mora Oral and Maxillofacial Pathologist  CHRONIC BRONCHITIS Chronic bronchitis is as persistent cough with sputum production for at least 3 months in at least 2 consecutive years, in the absence of any other identifiable cause. Chronic bronchitis, so common among habitual smokers and inhabitants of smog- laden cities. When persistent for years, it may – Progress to COPD, – Lead to cor pulmonale and heart failure, – Cause atypical metaplasia and dysplasia of the respiratory epithelium, providing a rich soil for cancerous transformation. Dr. Danny Mora Oral and Maxillofacial Pathologist CHRONIC BRONCHITIS Long-standing irritation by inhaled substances such as tobacco smoke (90% of patients are smokers), and dust from grain, cotton, and silica. Chronic bronchitis starts with hypersecretion of mucus in the large airways, associated with hypertrophy of the submucosal glands in the trachea and bronchi. There is also a marked increase in goblet cells of small airways—small bronchi and bronchioles—leading to excessive mucus production that contributes to airway obstruction. It is thought that both the submucosal gland hypertrophy and the increase in goblet cells are protective metaplastic reactions against tobacco smoke or other pollutants Dr. Danny Mora Oral and Maxillofacial Pathologist  Chronic Bronchitis The cardinal symptom of chronic bronchitis is a persistent cough productive of sputum. Long-standing severe chronic bronchitis commonly leads to corpulmonale with cardiac failure. Death may also result from further impairment of respiratory function due to superimposed acute infections. Dr. Danny Mora Oral and Maxillofacial Pathologist  Asthma ⦿ Is a chronic inflammatory disorder of the airways that causes recurrent episodes of wheezing, chest tightness, breathlessness, and cough. ⦿ Genetic predisposition to type I hypersensitivity. ⦿ Cytologic examination of sputum after an asthmatic attack shows ⚫ Eosinophils, ⚫ Charcot-Leyden crystals (orange, elongated, rhomboid crystals formed by degranulation of eosinophils) ⚫ Curshmann's spirals (dark staining core surrounded by lighter mucous). ⦿ Biopsy is rarely done. Dr. Danny Mora Oral and Maxillofacial Pathologist  Asthma In patients dying of status asthmatics the lungs are over- expanded and small airways are occluded by mucoid secretions. There is a variable amount of bronchiolar inflammation including eosinophilic infiltrates. Mucus glands are with hyperplasia of bronchial and bronchiolar smooth muscle. Dr. Danny Mora Oral and Maxillofacial Pathologist Lungsare the hyperinflated ina patient who died of status asthmaticus. Dr. Danny Mora Oral and Maxillofacial Pathologist Mucus plug fromasthma Dr. Danny Mora Oral and Maxillofacial Pathologist Typesof Asthma Atopic Asthma. – Most common type of asthma – Type I, IgE-mediated hypersensitivity reaction. – The disease usually begins in childhood and is triggered by environmental allergens, such as dusts, pollens, roach or animal dander, and foods. – Atopic asthma may also be diagnosed based on evidence of allergen sensitization by serum radioallergosorbent tests (called RAST), which identify the presence of IgE specific for a panel of allergens. Dr. Danny Mora Oral and Maxillofacial Pathologist  Typesof Asthma Non-Atopic Asthma. – The second group of individuals with asthma do not have evidence of allergen sensitization, and skin test results are usually negative. – A positive family history of asthma is less common in these patients. – Respiratory infections due to viruses (e.g., rhinovirus, parainfluenza virus) are common triggers in non-atopic asthma. – Hyperirritability of the bronchial tree probably underlies their asthma. – It is thought that virus-induced inflammation of the respiratory mucosa lowers the threshold of the subepithelial vagal receptors to irritants. Dr. Danny Mora Oral and Maxillofacial Pathologist Typesof Asthma Drug-Induced Asthma. – Aspirin-sensitive asthma is an uncommon yet fascinating type, occurring in individuals with recurrent rhinitis and nasal polyps. These individuals are exquisitely sensitive to small doses of aspirin as well as other nonsteroidal anti-inflammatory medications, and they experience not only asthmatic attacks but also urticaria. It is probable that aspirin triggers asthma in these patients by inhibiting the cyclooxygenase pathway of arachidonic acid and elaboration of the bronchoconstrictor leukotrienes. Occupational Asthma. – This form of asthma is stimulated by fumes (epoxy resins, plastics), organic and chemical dusts (wood, cotton, platinum), gases (toluene), and other chemicals (formaldehyde, penicillin products). – Minute quantities of chemicals are required to induce the attack, which usually occurs after repeated exposure. Dr. Danny Mora Oral and Maxillofacial Pathologist Chronic Diffuse Interstitial (Restrictive) Diseases Chronic interstitial diseases are characterized predominantly by inflammation and fibrosis of the pulmonary connective tissue. Many of the entities are of unknown cause and pathogenesis, some have an intra- alveolar as well as an interstitial component, and there is frequent overlap in histologic features among the different conditions. These disorders account for about 15% of noninfectious pulmonary diseases. Patients have dyspnea, tachypnea, end- inspiratory crackles, and eventual cyanosis, without wheezing or other evidence of airway obstruction. Chest radiographs show bilateral infiltrative lesions in the form of small nodules, irregular lines, or ground-glass shadows. Dr. Danny Mora Oral and Maxillofacial Pathologist Idiopathic Pulmonary Fibrosis (IPF) Causative agent(s) of IPF remain unknown “repeated cycles” of epithelial activation/injury by some unidentified agent. There is inflammation and induction of T cell response characterized by the presence of eosinophils, mast cells, IL-4 and IL-13 in the lesions. The significance of this inflammatory response is unknown. Abnormal epithelial repair at these sites gives rise to exuberant fibroblastic/myofibroblastic proliferation. Dr. Danny Mora Oral and Maxillofacial Pathologist Pneumoconiosis Pneumoconiosis is a non-neoplastic lung reaction to inhalation of mineral dusts encountered in the workplace and diseases induced by organic as well as inorganic particulates and chemical fumes and vapors. Studies have found increased morbidity (e.g., asthma incidence) and mortality rates in populations that are exposed to high ambient air particulate levels, leading to calls for greater efforts to reduce the levels of particulates in urban air. The development of a pneumoconiosis depends on – The amount of dust retained in the lung and airways; – The size and shape of the particles – Particle solubility and physiochemical reactivity – The possible additional effects of other irritants (e.g., concomitant tobacco smoking) Dr. Danny Mora Oral and Maxillofacial Pathologist  Pneumoconiosis Mineral Dusts Chemical Fumes and vapors Coal dust Nitrous oxide Silica Sulfur dioxide Asbestos Ammonia Beryllium Benzene Organic dusts Insecticides Moldy hay Bagassi Bird droppings Cotton Red cedar dust Dr. Danny Mora Oral and Maxillofacial Pathologist  Silicosis Silicosis is a lung disease caused by inhalation of crystalline silicon dioxide (silica). The most prevalent chronic occupational disease in the world. Presents after decades of exposure as a slowly progressing, nodular, fibrosing pneumoconiosis. Especially sandblasters and many mine workers. Less commonly, heavy exposure over months to a few years can result in acute silicosis, a disorder characterized by the accumulation of abundant lipoproteinaceous material within alveoli Silica, crystalline form (including quartz, crystobalite, and tridymite), are much more fibrogenic. Within the macrophages silica causes activation and release of mediators. – IL-1, TNF, fibronectin, lipid mediators, oxygen-derived free radicals, and fibrogenic cytokines. Dr. Danny Mora Oral and Maxillofacial Pathologist Asbestosrelated diseases Asbestos is a family of crystalline hydrated silicates that form fibers. Occupational exposure to asbestos is linked to: – Localized fibrous plaques or, rarely, diffuse pleural fibrosis – Pleural effusions – Parenchymal interstitial fibrosis (asbestosis) – Lung carcinoma – Mesotheliomas – Laryngeal and perhaps other extrapulmonary neoplasms, including colon carcinomas An increased incidence of asbestos-related cancer in family members of asbestos workers has alerted the general public to the potential hazards of asbestos in the environment. Dr. Danny Mora Oral and Maxillofacial Pathologist Pathogenesis of Asbestos There are two forms of asbestos: serpentine and amphibole. The serpentine chrysotile chemical form accounts for most of the asbestos used in industry. Amphiboles, even though less prevalent, are more pathogenic than chrysotiles particularly with respect to induction of malignant pleural tumors (mesotheliomas). Increasing doses are associated with a higher incidence of all asbestos-related diseases except mesothelioma, which is only associated with amphibole exposure. Asbestos can also act as a tumor initiator and promoter. Some of its oncogenic effects are mediated by reactive free radicals generated by asbestos fibers, which preferentially localize in the distal lung, close to the mesothelial layers. One study of asbestos workers found a fivefold increase of lung carcinoma with asbestos exposure alone, while asbestos exposure and smoking together led to a 55- fold increase in the risk of lung cancer. Dr. Danny Mora Oral and Maxillofacial Pathologist Asbestosis-morphology Asbestos bodies appear as golden brown, fusiform or beaded rods with a translucent center and consist of asbestos fibers coated with an iron-containing proteinaceous material. Asbestosis begins in the lower lobes and subpleurally. Pleural plaques, the most common manifestation of asbestos exposure, are well-circumscribed plaques of dense collagen Both lung carcinomas and mesotheliomas (pleural and peritoneal) develop in workers exposed to asbestos. The risk of lung carcinoma is increased about fivefold for asbestos workers; the relative risk of mesotheliomas, normally a rare tumor (2 to 17 cases per 1 million persons), is more than 1000-fold greater. Concomitant cigarette smoking greatly increases the risk of lung carcinoma but not that of mesothelioma. Produces: – Diffuse pulmonary interstitial fibrosis Dr. Danny Mora Oral and Maxillofacial Pathologist AsbestosBody Dr. Danny Mora Oral and Maxillofacial Pathologist  Vascular Lung Diseases Thromboembolism,hemorrhage and infarction Thrombus – Usual source is thrombi in the deep veins of the leg (95%) – Due to prolonged inmovilization like hospitalized patients, severe burns, trauma, and fractures. Dr. Danny Mora Oral and Maxillofacial Pathologist  Saddle thrombus is a blood clot which is seen at the bifurcation of the pulmonary artery. – This results in sudden death with no pathologic change in the lungs. Embolus – Smaller emboli lodge distally depending on their size. – There is hemorrhage into the adjacent lung parenchyma. – Emboli may contain tumor, infection, fat or bone marrow. Dr. Danny Mora Oral and Maxillofacial Pathologist Thromboembolism Dr. Danny Mora Oral and Maxillofacial Pathologist Morphology Only about 10% of emboli actually cause infarction, which occurs when the circulation is already inadequate About three fourths of all infarcts affect the lower lobes The pulmonary infarct is classically hemorrhagic and appears as a raised, red-blue area in the early stages The red cells begin to lyse within 48 hours, and the infarct becomes paler and eventually red-brown as hemosiderin is produced. With time, fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a contracted scar. Histologically, the diagnostic feature of acute pulmonary infarction is the ischemic necrosis of the lung substance within the area of hemorrhage, affecting the alveolar walls, bronchioles, and vessels. Dr. Danny Mora Oral and Maxillofacial Pathologist  Pulmonary Infarction Dr. Danny Mora Oral and Maxillofacial Pathologist  Amyloidosis Systemic disease related to abnormal protein folding. The lung architecture is well- reserved with diffuse thickening of the alveolar septa by deposition of amorphous proteinaceous eosinophilic material. The amyloid deposits may be diffuse and uniform and consist of multiple interstitial nodules. Dr. Danny Mora Oral and Maxillofacial Pathologist  Amyloidosis The blood vessels, and occasionally pleura, may also contain amyloid deposits. Amyloid has apple-green birefringence when congo red stained section is polarized. On EM it has a characteristic fibrillar structure. Dr. Danny Mora Oral and Maxillofacial Pathologist Amyloid is composed of a "beta-pleated sheet" of fibrils, seen here as irregular grey material. Electron microscopy Dr. Danny Mora Oral and Maxillofacial Pathologist Community-Acquired Acute Pneumonias Community-acquired pneumonias may be bacterial or viral. Often, the bacterial infection follows an upper respiratory tract viral infection. Bacterial invasion of the lung parenchyma causes the alveoli to be filled with an inflammatory exudate, thus causing consolidation (“solidification”) of the pulmonary tissue. Predisposing conditions include extremes of age, chronic diseases (congestive heart failure, COPD, and diabetes), congenital or acquired immune deficiencies, and decreased or absent splenic function (sickle cell disease or post-splenectomy, which puts the patient at risk for infection with encapsulated bacteria such as pneumococcus). Dr. Danny Mora Oral and Maxillofacial Pathologist  Infections Streptococcus pneumoniae – Streptococcus pneumoniae, or pneumococcus, is the most common cause of community-acquired acute pneumonia. – Examination of Gram-stained sputum is an important step in the diagnosis of acute pneumonia. – The presence of numerous neutrophils containing the typical gram-positive, lancet-shaped diplococci supports the diagnosis of pneumococcal pneumonia. – Pneumococcal vaccines containing capsular polysaccharides from the common serotypes are used in patients at high risk. Dr. Danny Mora Oral and Maxillofacial Pathologist  Infections Haemophilus influenzae – Haemophilus influenzae is a pleomorphic, gram-negative organism that is a major cause of life-threatening acute lower respiratory tract infections and meningitis in young children. – In adults it is a very common cause of community-acquired acute pneumonia. – It exists in two forms: encapsulated (5%) and unencapsulated (95%). – They spread along the surface of the upper respiratory tract and produce otitis media, sinusitis, and bronchopneumonia. Dr. Danny Mora Oral and Maxillofacial Pathologist  Infections Human Coronaviruses Coronaviruses are enveloped, positive-sense RNA viruses that infect humans and several other vertebrate species. Weakly pathogenic coronaviruses cause mild cold-like upper respiratory tract infections, while highly pathogenic ones may cause severe, often fatal pneumonia. An example of a highly pathogenic type is SARS-CoV-2, a strain that emerged in late 2019 in China that is producing a still evolving pandemic as of early 2020. Highly pathogenic coronaviruses like SARS-CoV-2 bind the ACE2 protein on the surface of pulmonary alveolar epithelial cells, explaining the tropism of these viruses for the lung. With highly pathogenic forms in susceptible hosts, typically older individuals with comorbid conditions, the host immune response and locally released cytokines often produce acute lung injury and ARDS. Dr. Danny Mora Oral and Maxillofacial Pathologist  Acute BacterialPneumonia Culture and sensitivity results, extent of involvement and host resistance are m u c h more important than histologic changes. All bacterial pneumonias are characterized by presence of neutrophils in air spaces and small bronchioles. Dr. Danny Mora Oral and Maxillofacial Pathologist Acute Bacterial Pneumonia The lung appears red and consolidated (red hepatization) followed by grey-white appearance (grey hepatization) due to lysis of RBC's , followed by either complete resolution or fibrosis. Bronchopneumonia is patchy involving only small bronchioles and adjacent alveoli as compared to lobar pneumonia which involves one or more lobes. Complications of pneumonia include – Spread of infection to the pleural cavity, causing the intrapleural fibrinosuppurative reaction known as empyema; – Bacteremic dissemination to the heart valves, pericardium, brain, kidneys, spleen, or joints, causing metastatic abscesses, endocarditis, meningitis, or suppurative arthritis. Dr. Danny Mora Oral and Maxillofacial Pathologist Acute Bacterial Pneumonia Dr. Danny Mora Oral and Maxillofacial Pathologist  Hospital-Acquired Pneumonia – Hospital-acquired pneumonias are defined as pulmonary infections acquired in the course of a hospital stay. – They are common in patients with severe underlying disease, immunosuppression, prolonged antibiotic therapy, or invasive access devices such as intravascular catheters. Patients on mechanical ventilation are at particularly high risk. – Gram-negative rods (Enterobacteriaceae and Pseudomonas species) and S. aureus are the most common isolates; unlike community-acquired pneumonias, S. pneumoniae is not a major pathogen. Aspiration Pneumonia – Aspiration pneumonia occurs in markedly debilitated patients or those who aspirate gastric contents either while unconscious (e.g., after a stroke) or during repeated vomiting. – These patients have abnormal gag and swallowing reflexes that predispose to aspiration. – The resultant pneumonia is partly chemical because of the extremely irritating effects of the gastric acid, and partly bacterial (from the oral flora). Dr. Danny Mora Oral and Maxillofacial Pathologist  Tuberculosis The histologic hallmark is caseating granulomas with Langhan's type giant cells. The granuloma is a rounded collection of macrophages and lymphocytes containing multinucleated giant cells, the nuclei of which are arranged at the periphery in a horse-shoe shape. Acid-fast bacilli can sometimes be demonstrated by the Zeihl- Neelson stain on tissue sections. Cultures are much more sensitive. Secondary TB has a much higher incidence of large areas of caseating necrosis. Primary and secondary TB are histologically similar. Dr. Danny Mora Oral and Maxillofacial Pathologist  Tuberculosis Dr. Danny Mora Oral and Maxillofacial Pathologist  Tuberculosis Dr. Danny Mora Oral and Maxillofacial Pathologist  FungalInfections All of the following are GMS and PAS positive. – Candidiasis: Pseudohyphae and budding yeasts. – Aspergillosis: Septate, true hypae with acute angle branding. – Mucormycosis: Non-septate, true hyphae, broad, ribbon-like, with wide angle branching. – Histoplasmosis: Granulomatous inflammation caused by small budding yeasts (3-5 microns). Dr. Danny Mora Oral and Maxillofacial Pathologist  Fungal Infections – Blastomycosis: Mixed acute and granulomatous inflammation caused by large budding yeasts, thick-walled with broad-based bud. – Coccidioidomycosis: Granulomatous inflammation caused by variable sized daughter cysts within large cyst wall. – Cryptococcosis: Minimal or no inflammation, budding yeasts with mucin positive capsule (which looks like a halo on H&E) and thin-based buds. Dr. Danny Mora Oral and Maxillofacial Pathologist Pneumocystis pneumonia Typical histologic picture shows intraalveolar, acellular, frothy material with minimal inflammation. Silver stain (GMS) shows 7-8 micron, non-budding cysts which may be cup-shaped or helmet-shaped. Some have central black dot. Dr. Danny Mora Oral and Maxillofacial Pathologist  LungTransplantation Indications for transplantation includes all non- neoplastic terminal lung diseases The most common indications are end-stage emphysema, idiopathic pulmonary fibrosis, cystic fibrosis, and idiopathic/familial pulmonary arterial hypertension. When bilateral chronic infection is present (e.g., cystic fibrosis, bronchiectasis), both lungs of the recipient must be replaced to remove the reservoir of infection. Dr. Danny Mora Oral and Maxillofacial Pathologist  LungCancer Lung cancer is currently the most frequently diagnosed major cancer in the world and the most common cause of cancer mortality worldwide. Due to the carcinogenic effects of cigarette smoke. Accounts for about 15% of cancer diagnoses and 29% of cancer- related deaths. Of the wide variety of benign and malignant tumors that may arise in the lung, 90% to 95% are carcinomas, about 5% are carcinoid tumors, and 2%to 5%are mesenchymal and other miscellaneous neoplasms. Dr. Danny Mora Oral and Maxillofacial Pathologist  Lung Cancer Since the early 1990s lung cancer incidence and mortality rates have been decreasing in men. Since 1987 more women have died each year of lung cancer than of breast cancer. Most often between ages 40 and 70 years, with a peak incidence in the 50s or 60s. Only 2%of all cases appear before the age of 40. The 5-year rate for all stages combined is only 16% Dr. Danny Mora Oral and Maxillofacial Pathologist  Tobacco Smoking About 80% of lung cancers occur in active smokers or those who stopped recently, and there is a nearly linear correlation between the frequency of lung cancer and pack-years of cigarette smoking. The increased risk is 60 times greater in habitual heavy smokers (two packs a day for 20 years) than in nonsmokers. Women are more susceptible to carcinogens in tobacco than men. Although cessation of smoking decreases the risk for lung cancer over time, it may never return to baseline levels. The long-term effects of electronic cigarette aerosols are not known, as “vaping” is a relatively recent phenomenon Statistical evidence is most compelling: 87% of lung carcinomas occur in active smokers or those who stopped recently. Average smokers of cigarettes have a tenfold greater risk of developing lung cancer, and heavy smokers (more than 40 cigarettes per day for several years) have a 60-fold greater risk. Second hand smoke, or environmental tobacco smoke, contains numerous human carcinogens for which there is no safe level of exposure. Dr. Danny Mora Oral and Maxillofacial Pathologist  IndustrialHazards High-dose ionizing radiation is carcinogenic. Survivors of the Hiroshima and Nagasaki atomic bomb blasts. Uranium is weakly radioactive, but lung cancer rates among nonsmoking uranium miners are four times higher Dr. Danny Mora Oral and Maxillofacial Pathologist  Asbestos. – Those who do not smoke have a five times greater risk of developing lung cancer than do nonsmoking control subjects, and those who smoke have a 50 to 90 times greater risk. The latent period before the development of lung cancer is 10 to 30 years. Air Pollution. – Atmospheric pollutants may play some role in the increased incidence of lung carcinoma today. – Attention has been drawn to the potential problem of indoor air pollution, especially by radon. – Radon is a ubiquitous radioactive gas that has been linked epidemiologically to increased lung cancer in miners exposed to relatively high concentrations. Dr. Danny Mora Oral and Maxillofacial Pathologist  Molecular Genetics. – It has been estimated that 10 to 20 genetic mutations have occurred by the time the tumor is clinically apparent. – The dominant oncogenes that are frequently involved in lung cancer include c-MYC, KRAS, EGFR, c-MET, and c-KIT. – The commonly deleted or inactivated tumor suppressor genes include p53, RB1, p16(INK4a), and multiple loci on chromosome 3p. – Telomerase activity is increased in over 80% of lung tumor tissues. Occasional familial clustering – It should also be pointed out that 25% of lung cancers worldwide arise in nonsmokers and these are pathogenetically distinct. – They occur more commonly in women, and most are adenocarcinomas. – EGFR mutations, almost never have KRAS mutations and p53 mutations. Dr. Danny Mora Oral and Maxillofacial Pathologist  Lung Cancer in Never Smokers. – The WHO estimates that 25% of lung cancer worldwide occurs in never smokers. – These cancers occur more commonly in women and most are adenocarcinomas. – Cancers in nonsmokers are more likely to have EGFR mutations, and almost never have KRAS mutations; – TP53mutations are not uncommon, but occur less frequently than in smoking-related cancers. Precursor (Preinvasive) Lesions. – Four types of morphologic precursor epithelial lesions are recognized: Squamous dysplasia and carcinoma in situ Atypical adenomatous hyperplasia Adenocarcinoma in situ Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia – The term precursor does not imply that progression to cancer is inevitable. – Currently it is not possible to distinguish between precursor lesions that progress and those that remain localized or regress. Dr. Danny Mora Oral and Maxillofacial Pathologist  Classification Adenocarcinoma (50%) Squamous cell carcinoma (20%) Small cell carcinoma (15%) Large cell carcinoma (2%) Other (13%) Dr. Danny Mora Oral and Maxillofacial Pathologist Tumor Classification Adenocarcinoma 1. Lepidic, acinar, micropapillary, papillary, solid (according to predominant pattern) 2. Invasive mucinous adenocarcinoma 3. Minimally invasive adenocarcinoma (nonmucinous, mucinous) Squamous cell carcinoma 1. Keratinizing, nonkeratinizing, basaloid Neuroendocrine tumors 1. Small cell carcinoma 2. Combined small cell carcinoma 3. Large cell neuroendocrine carcinoma 4. Combined large-cell neuroendocrine carcinoma 5. Carcinoid tumor 6. Typical, atypical Other uncommon types 1. Large cell carcinoma 2. Adenosquamous carcinoma 3. Sarcomatoid carcinoma 4. Pleomorphic, spindle cell, giant cell carcinoma, carcinosarcoma, pulmonary blastoma 5. Others such as lymphoepithelioma-like carcinoma and NUT carcinoma Dr. Danny Mora Oral and Maxillofacial Pathologist 6. Salivary gland–type tumors  Adenocarcinoma A malignant epithelial tumor with glandular differentiation or mucin production by the tumor cells. Adenocarcinomas grow in various patterns, including acinar, papillary, bronchioloalveolar, and solid with mucin formation. Adenocarcinoma is the most common type of lung cancer in women and nonsmokers. Usually more peripherally located, and tend to be smaller. They vary histologically from well-differentiated tumors with obvious glandular elements to papillary lesions resembling other papillary carcinomas to solid masses with only occasional mucin-producing glands and cells. Dr. Danny Mora Oral and Maxillofacial Pathologist Squamous cell carcinoma ⦿ Squamous cell carcinoma is most commonly found in men and is closely correlated with a smoking history. ⦿ Histologically, this tumor is characterized by the presence of keratinization and/or intercellular bridges. ⦿ Keratinization may take the form of squamous pearls or individual cells with markedly eosinophilic dense cytoplasm. ⦿ Most squamous cell carcinomas were seen to arise centrally from the segmental or subsegmental bronchi. ⦿ Squamous metaplasia, epithelial dysplasia, and foci of frank carcinoma in situ may be seen in bronchial epithelium adjacent to the tumor mass Dr. Danny Mora Oral and Maxillofacial Pathologist  This is a squamous cell carcinoma in which a portion of the tumor demonstrates central cavitation, probably because the tumor outgrew its blood supply. Dr. Danny Mora Oral and Maxillofacial Pathologist Histology of well differentiated Squamous carcinoma of lung with formation of keratin pearls Dr. Danny Mora Oral and Maxillofacial Pathologist  SmallCell Carcinoma Highly malignant tumor with a strong relationship to cigarette smoking; 1%occurs in nonsmokers They may arise in major bronchi or in the periphery of the lung. They are the most aggressive of lung tumors, metastasizing widely and virtually always proving to be fatal. Necrosis is common and often extensive. Neuroendocrine markers such as chromogranin, synaptophysin, and CD57, and the ability of some of these tumors to secrete hormones (e.g., parathormone-related protein, a cause of paraneoplastic hypercalcemia) suggest that this tumor originates from neuroendocrine progenitor cells Associated with ectopic hormone production High levels of the anti-apoptotic protein BCL2 in 90% of tumors Dr. Danny Mora Oral and Maxillofacial Pathologist  Clinical course fromBronchogenic Carcinoma ⦿ Aggressive and insidious ⦿ Overall 5-year survival rate is only 16% ⦿ The 5-year survival rate is 52% for cases detected when the disease is still localized, 22% when there is regional metastasis and only 4%with distant metastases ⦿ Paraneoplastic syndrome ⚫Inappropriate ADH secretion ⚫ACTH producing Cushing Syndrome ⚫Hypercalcemia ⚫Calcitonin produce hypocalcemia ⚫Gonadotrophins produce gynecomastia ⚫Serotonin and bradikinin production associated to carcinoid Dr. Danny Mora Oral and Maxillofacial Pathologist  Metastases ⦿ Metastatic lung disease is more frequent than primary carcinoma ⦿ Are typically rounded and multiple. ⦿ The histology is usually the same as of the primary tumor. ⦿ Metastases to the lungs are more common even than primary lung neoplasms ⦿ The nodules are usually in the periphery and do not cause major obstruction ⦿ Most frequent: ⦿ Breast ⦿ Liver ⦿ Colon ⦿ Prostate ⦿ Kidney Dr. Danny Mora Oral and Maxillofacial Pathologist  Multiple variably-sized masses are seen in all lung fields. These tan-white nodules are characteristic for metastatic carcinoma. Dr. Danny Mora Oral and Maxillofacial Pathologist  Malignant Mesothelioma Inthe thorax arise from either the visceral or the parietal pleura. Increased incidence among people with heavy exposure to asbestos Incoastal areas with shipping industriesin the United Statesand Great Britain, and in Canadian, Australian, and South African mining areas, as many as 90% of reported mesotheliomas are asbestos-related. The lifetimeriskof developing mesothelioma in heavily exposed individuals isas high as 7%to 10%. Latent period of 25to 45years No increased riskof mesothelioma in asbestos workerswho smoke. 60%to 80%of malignant mesotheliomas have deletions in chromosomes 1p, 3p, 6q, 9p, or 22q, and 31%have p16 mutations. Dr. Danny Mora Oral and Maxillofacial Pathologist  Mesothelioma Dr. Danny Mora Oral and Maxillofacial Pathologist  Mesothelioma Complains of chest pain, dyspnea, and, as noted, recurrent pleural effusions. The lung is invaded directly, and there is often metastatic spread to the hilar lymph nodes and, eventually, to the liver and other distant organs. 50% of patients die within 12 months of diagnosis, and few survive longer than 2 years. Aggressive therapy (extrapleural pneumonectomy, chemotherapy, radiation therapy) seems to improve this poor prognosis in some patients with epithelioid mesothelioma. Can also arise in the peritoneum, pericardium, tunica vaginalis, and genital tract Peritoneal mesotheliomas are particularly related to heavy asbestos exposure; 50% of such patients also have pulmonary fibrosis. Dr. Danny Mora Oral and Maxillofacial Pathologist  Questions? Dr. Danny Mora Oral and Maxillofacial Pathologist