Asthma - morphology ARDS. Acute restrictive lung disease. Diffuse pulmonary diseases. Pulmonary fibrosis, asbestosis and mesothelioma

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1 Diffuse pulmonary diseases Pulmonary fibrosis, asbestosis and mesothelioma 2012 by MB Obstructive Limitation of air flow, resulting from obstruction at any level (asthma airway narrowing; emphysema loss of elastic recoil, bronchitis, cystic fibrosis) Restrictive Reduced expansion of lung, decreased lung capacity extrapulmonary disorders (severe obesity, Guillain-Barre syndrome) acute or chronic interstitial lung disease Obstructive lung diseases - asthma Episodic, reversible bronchospasm resulting from exaggerated bronchoconstrictor response to various stimuli extrinsic: initiated by a type I hypersensitivity reaction; most common-atopic (two first decades, elevated serum IgE), or Intrinsic: nonimmune mechanisms (aspirin, stress, infections, cold, exercise) Asthma - morphology Macroscopic finding: occlusion of bronchi and bronchioles by thick, mucus plugs (containing whorls of shed epithelium: Curschmann spirals and eosinophil crystalloids) Other microscopic findings: increase in size of mucous glands and goblet cells, necrosis and shedding of epithelial cells,thickened basement membrane, hypertrophy of the smooth muscles in the bronchial wall, inflammatory infiltrate with eosinophils Acute restrictive lung disease Acute respiratory distress syndrome - ARDS A progressive respiratory failure defined by acute onset of dyspnoe hypoxemia (low arterial oxygen pressure) absence of primary left-sided heart failure bilateral pulmonary changes on radiographs ARDS causes pneumonia aspiration of gastric contents sepsis shock trauma fat embolism drug overdose uremia acute pancreatitis

2 Chronic restrictive (interstitial) lung disease About 150 causes! Asbestosis, silicosis, drugs (Metotrexate), ionizing radiation, sarcoidosis, SLE, idiopathic? A 63-year-old man has had worsening dyspnea with nonproductive cough for the past 9 months. He is afebrile and normotensive. His heart rate is 77/min and regular. On ausculatations, diffuse dry crackles are heard in all lung fields. A chest rtg shows irregular opacifications throught both lungs. A transbronchial biopsy specimen is shown:?? Laboratory studies include negative serologic tests for ANA and ANCA. Despite glucocorticoid therapy, his condition does not improve and he dies 2 years later. Which of the following is the most likely diagnosis? A.ARDS B.Goodpasture syndrome C.idiopathic pulmonary fibrosis D.scleroderma E.Wegener granulomatosis?? ARDS? NO. Acute respiratory distress syndrome follows acute lung injury in very ill patients, typically those in an intesnsive care unit.

3 ? Goodpasture syndrome NO. Goodpasture syndrome is characterized by diffuse pulmonary hemorrhage.? Wegener granulomatosis produces necrotizing granulomatous inflammation and the ANCA test is often positive.? Pulmonary fibrosis leads to progressive restrictive lung disease The antigen that incites the inflammatory process with activated macrophage release of cytokines such as fibroblast growth factor (fibrosis) is unknown Genetic abnormalities in surfactant protein (in some familial forms of IPF)? Pulmonary fibrosis intraalveolar, interstitial, obliterative Intraalveolar fibrosis Carnificatio pulmonis Complication of pneumonia: organisation of an alveolar exudate, when bacterial pneumonia fails to resolve (postpneumonic carnification) Presence within the alveoli myxoid granulation tissue rich in fibroblasts but containing little collagen granulation tissue occupies the alveoli (by B.Corrin)

4 Obliterative fibrosis Interstitial fibrosis ARDS severe injury fibrin-rich exudate organisation complete obliteration Involves the interstitial compartment of the alveolar walls and largely spares the air spaces This pattern of fibrosis is unlikely to resolve. Interstitial fibrosis (by B.Corrin) The causes of interstitial fibrosis 1. formation of exudates or transsudates long-standing oedema in mitral stenosis idiopathic (Hamman-Rich) asbestosis 2. formation of granulomas (mostly pneumoconioses) sarcoidosis allergic alveolitis silicosis berylliosis Pneumoconioses A number of different types of occupational lung diseases in which inhalation of mineral dust results in pulmonary fibrosis (or inflammation) Accounts for ~ 25% of cases of chronic interstitial lung disease Coal dust is the least fibrogenic particle Silica, asbestos and beryllium are very fibrogenic Pneumoconioses - silicosis Silicosis most common occupational disease in the world Quartz (crystalline silicone dioxide); sources: casting metal, sandblasting, working in mines Highly fibrogenic, deposits in the upper lungs (activates macrophages, release of cytokines that stimulate fibrogenesis) Complications: cor pulmonale, increased risk for developing lung cancer and TB

5 Asbestosis Def. Pulmonary fibrosis caused by asbestos (usually attributable to long-term exposure over periods of years) Asbestos term for over 30 fibrous silicates Main forms of asbestos of commercial importance: Amosite (brown asbestos) Crocidolite (blue asbestos) the most dangerous Asbestos The inhalation of asbestos fibers was first linked to the development of lung disease in 1890 (Because of its flexibility, and resistance to heat, it became widely used in industry) Legislation controlling exposure was introduced The peak global incidence of asbestos-related disease is expected to occur 30 to 40 years after the period of peak usage (the 1960s and 1970s) For diffuse malignant mesothelioma, the condition with the longest latency, the incidence is expected to rise in Europe until 2020 (BrJCancer 1999;79:666) Asbestos Asbestos bodies Exposure direct (miners, electrical and shipyard workers, plumbers, building engineers) indirect (families of asbestos workers) ambient ( due to general atmospheric pollution) fibres of 100 µm may reach the alveoli they become coated with a protein rich in iron some fibres remain naked (no tissue reaction) carcinogenic effect? Asbestos bodies Asbestosis Clinical features Slowly developing breathlessness Right - sided heart failure (cor pulmonale) Seen by light microscopy Scanning electron microscopy (by B.Corrin)

6 Cor pulmonale (pulmonary heart disease) Disease of the right-sided cardiac chambers caused by pulmonary hypertension resulting from pulmonary parenchymal or vascular disease (pulmonary hypertension caused by left ventricular failure are excluded from this definition) The most common cause of the chronic cor pulmonare is chronic obstructive lung disease (emphysema, chronic bronchitis, bronchiectasis) Disorders that predispose to cor pulmonale Diseases of the lung (obstructive lung disease, interstitial fibrosis, persistent atelectasis, cystic fibrosis) Diseases of pulmonary vessels (pulmonary emboli, Wegener granulomatosis, drug- or radiation-induced sclerosis Disorders affecting chest movement (kyfoscoliosis, marked obesity, Guillain- Barre s.) Asbestos-related lung disease Asbestosis: a fibrotic lung disease, presenting with dyspnea and dry cough, characterized by a mild fibrosis Benign pleural disease (pleural plaques) Lung cancer Asbestosis fine interstitial fibrosis beneath the pleura Asbestosis Asbestos bodies histological appearances interstitial fibrosis of alveolar walls interstitial pneumonitis (subpleural) increased number of alveolar macrophages numerous asbestos bodies degeneration of the alveolar epithelium and endothelium USA- the minimum criteria for diagnosing asbestosis: Peribronchiolar fibrosis and at least 2 asbestos bodies in detail

7 Pathogenesis Asbestosis increased prevalence of circulating autoantibodies complement-dependent activation of macrophages macrophages secrete fibroblasts-stimulating factors epithelial damage (due to phagocyte generation of free radicals) Benign pleural disease The most common pathologic pulmonary response to asbestos inhalation Over time, collagen is deposited in the pleura and may calcify Most plaques are asymptomatic Unilateral pleural effusions: manifestation of pleural disease years after exposure Pleural effusion may be a symptom of tbc, bronchogenic carcinoma or malignant mesothelioma, so benign pleural effusion is a diagnosis of exclusion! Asbestos pneumoconiosis -pleural plaques Parietal pleura Marked pleural fibrosis Asbestos-related lung disease The American Thoracic Society recommends performing chest radiography and pulmonary function testing every three to five years in patients with disease It may help identify lung cancer earlier Detection of cancer in asbestosis patients using SELDI-TOF Surface-Enhanced-Laser Desorption/ionization Time of Flight Mass Spectrometry: one of the currently used techniques to identify proteins that can be used as blood biomarkers to identify asbestosis patients at risk of developing lung cancer Biomarkers, 2011 Mar 16(2) Asbestos-related cancer Carcinoma of the lung of the pleura and peritoneum Asbestos + cigarette smoke = multiplicative effect (lung cancer)

8 Asbestos-related cancer Asbestos induced pleural fibrosis asbestosis associated with carcinoma of the lung diffuse pleural thickening, may be followed by mesothelioma Now recognized to be one of the most important occupational diseases Incidence has been steadily rising, now accounts for about 1% of all cancer deaths in industrialized countries. in Japan: relevance to occupational asbestos exposure 442 cases of malignant mesothelioma ( ) with a median age of 68 years 79,2% of cases were caused by asbestos exposure Am J Ind Med Nov; 53(11) 1081 Diffuse malignant mesothelioma Def: A malignant tumor arising in the pleura from mesothelial cells and showing a diffuse pattern of growth. (WHO 2003) Etiology Asbestos Non-asbestos fibres Therapeutic radiation Processes leading to intense pleural scarring Simian monkey virus SV 40? SV 40 Some polio vaccines used during were contaminated with SV40. This infection has spread to millions of people in North America and most European countries., brain tumors, bone sarcomas, non-hodgkin lymphomas frequently contain sequences of SV40

9 SV 40 SV40 is highly oncogenic in rodents Whether a latent infection is a causal factor of human mesothelioma, remains to be assessed Clinical symptoms Dyspnoea due to a pleural effusion Chest wall pain Weight loss, weakness Diagnostic procedures Pleural biopsies obtained by thoracoscopy Pleural fluid cytology (negative in 50%) Tumor spread Multiple small nodules on the parietal pleura confluent nodules fusion of visceral and parietal pleura interlobar fissures lung chest wall diaphragm- metastases to hilar and mediastinal lymph nodes opposite pleural cavity - hematogenous spread (liver, adrenals, bone, brain) Histopathology Numerous morphologic variants! spread along interlobar fissures Epithelioid Sarcomatoid Desmoplastic Biphasic

10 Epithelioid mesothelioma Epithelioid mesothelioma Abundant eosinophilic cytoplasm, vesicular chromatin, prominent nucleoli Patterns: Tubulopapillary (psammoma bodies) Microglandular (signet-ring cells with no mucin) Sheet-like (solid, nests of cells) tubular Epithelioid mesothelioma Epithelioid mesothelioma papillary solid Epithelioid mesothelioma can mimic: non-hodgkin lymphoma, large cell or small cell carcinoma, metastatic renal cell carcinoma, metastatic adenocarcinoma or melanoma; reactive mesothelial hyperplasia Immunohistochemistry! cytokeratin CD 15 EMA HMB, melan A Sarcomatoid mesothelioma Spindle cells arranged in fascicles (resembles fibrosarcoma) Anaplasia and bizarre cells (resembles MFH) Osteoid (osteosarcoma) May be positive for: cytokeratin, vimentin, actin, S-100

11 Sarcomatoid mesothelioma Sarcomatoid mesothelioma Spindle cells arranged in fascicles, fat invasion Desmoplastic mesothelioma Dense collagenized tissue, atypical cells arranged in storiform pattern (resembles organizing pleuritis) Desmoplastic mesothelioma cellular pleomorphism Desmoplastic mesothelioma fat invasion Desmoplastic mesothelioma storiform pattern

12 Biphasic mesothelioma Contain both epithelioid and sarcomatoid or any other pattern (at least 10%) Prognosis Good prognostic indicators: young age, epithelioid subtype, lack of chest pain The worse prognosis: purely sarcomatoid type Well differentiated papillary mesothelioma Progression of the disease is not appreciably modified by treatment. A few patients survive longer than 2 years from the time of diagnosis Tumor with paplillary architecture and tendency toward superficial spread without invasion Localized mesothelioma (solitary fibrous tumor) A rare tumor, localized nodular lesion without evidence of spread, but with the histological features of malignant one (spindle cells, cytokeratin-negative) There is no relationship to asbestos exposure or other environmental pathogrens Cured by surgical excision

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