Pulmonary Embolism Morphology

Pulmonary Embolism Morphology
Large emboli lodge in the main pulmonary artery or its major branches, or at the bifurcation as a “saddle embolus”. Sudden death often ensues, largely as a result of the blockage of blood flow through the lungs. Death may also be caused by acute failure of the right side of the heart (acute cor pulmonale). A saddle embolus

The pulmonary infarct is classically hemorrhagic and appears as a raised, red-blue area in the early stages. Often, the apposed pleural surface is covered by a fibrinous exudate. The red cells begin to lyse within 48 hours, and the infarct becomes paler and eventually red-brown as hemosiderin is produced. With the passage of time, fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a contracted scar. Recent, small, roughly wedge-shaped hemorrhagic pulmonary infarct.

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. If the infarct is caused by an infected embolus, it is modified by a more intense neutrophilic inflammatory reaction. Such lesions are referred to as septic infarcts, and some convert to abscesses.

Pulmonary Embolism Clinical Course
Findings on chest x-ray are variable and can be normal or disclose a pulmonary infarct, usually 12 to 36 hours after it has occurred, as a wedge-shaped infiltrate. The diagnosis of pulmonary embolism is usually made with spiral computed tomographic angiography. Occasionally, other diagnostic methods, such as ventilation perfusion scanning or pulmonary angiography are required. Deep vein thrombosis of the lower extremity can be diagnosed with duplex ultrasonography. Chest Spiral CT (with and without contrast agent) showing multiples filling defects of principal branches, due to acute and chronic pulmonary embolism.

Pulmonary Hypertension
Previous congenital or acquired heart disease Eg, PH occurs in patients with mitral stenosis an increase in left atrial pressure leads to an increase in pulmonary venous pressure and, consequently, to an increase in pulmonary artery pressure. “Fish mouth” mitral stenosis secondary to chronic rheumatic heart disease.

Pulmonary Hypertension Morphology
Vascular changes in pulmonary hypertension. Marked medial hypertrophy.

Vascular changes in pulmonary hypertension. Gross photograph of atheroma formation, a finding usually limited to large vessels.

Right ventricular hypertrophy

One extreme in the spectrum of pathologic changes (present most prominently in idiopathic and familial pulmonary arterial hypertension, unrepaired congenital heart disease with left- to-right shunts, and PH associated with drugs and HIV), is the plexiform lesion, so called because a tuft of capillary formations is present, producing a network, or web, that spans the lumens of dilated thin-walled, small arteries and may extend outside the vessel. Vascular changes in pulmonary hypertension. Plexiform lesion characteristic of advanced pulmonary hypertension seen in small arteries

Goodpasture Syndrome Morphology
In the classic case, the lungs are heavy, with areas of red-brown consolidation. Histologically, there is focal necrosis of alveolar walls associated with intra-alveolar hemorrhages. * Often the alveoli contain hemosiderin-laden macrophages. In later stages there may be fibrous thickening of the septae, hypertrophy of type II pneumocytes, and organization of blood in alveolar spaces.

Nasopharyngeal Carcinoma Morphology
On histologic examination, the keratinizing and nonkeratinizing squamous cell lesions resemble usual well-differentiated and poorly differentiated squamous cell carcinomas arising in other locations. Nasopharyngeal squamous cell carcinoma

Nasopharyngeal Carcinoma Morphology
The undifferentiated variant is composed of large epithelial cells with oval or round vesicular nuclei, prominent nucleoli, and indistinct cell borders disposed in a syncytium-like array. Admixed with the epithelial cells are abundant, mature, normal-appearing lymphocytes, which are predominantly T cells. Nasopharyngeal carcinoma, undifferentiated type. The syncytium-like nests of epithelium are surrounded by lymphocytes

Undifferentiated Nasopharyngeal Carcinoma

Reactive Nodules of the Larynx
Histologically, these are typically covered by squamous epithelium that may become keratotic, hyperplastic, or even slightly dysplastic. The core of the nodule is a loose myxoid connective tissue that may be variably fibrotic or punctuated by numerous vascular channels. Singer’s nodule, histology.

Squamous Papilloma and Papillomatosis
On histologic examination, the papillomas are made up of multiple slender, finger-like projections supported by central fibrovascular cores and covered by an orderly stratified squamous epithelium. When the papillomas are on the free edge of the vocal cord, trauma may lead to ulceration that can be accompanied by hemoptysis. Laryngeal papilloma

Sequence of Hyperplasia-Dysplasia-Carcinoma
Macroscopically, the epithelial changes vary from smooth, white or reddened focal thickenings, sometimes roughened by keratosis, to irregular verrucous or ulcerated white-pink lesions that are similar in appearance to carcinoma. Laryngeal hyperplasia/keratosis

Severe Epithelial Dysplasia of the Larynx
Arrow points to mitosis.

Carcinoma of the Larynx Morphology
Squamous cell carcinomas of the larynx follow the growth pattern of other squamous cell carcinomas. They begin as in situ lesions that later appear as pearly gray, wrinkled plaques on the mucosal surface, and ultimately are ulcerating and fungating. Laryngeal carcinoma. Note the large, ulcerated, fungating lesion involving the vocal cord and pyriform sinus.

Carcinoma of the Larynx Morphology
Histologically, the degree of anaplasia of laryngeal carcinomas is highly variable. Sometimes massive tumor giant cells and multiple bizarre mitotic figures are seen. Adjacent mucosa may demonstrate squamous cell hyperplasia with foci of dysplasia or carcinoma in situ. Laryngeal carcinoma. Histologic appearance of laryngeal squamous cell carcinoma. Note the atypical lining epithelium and invasive keratinizing cancer cells in the submucosa.

Inflammatory Pleural Effusions
Autopsy image, serofibrinous pleruritis

Empyema is characterized by loculated, yellow-green, creamy pus composed of masses of neutrophils admixed with other leukocytes. Although empyema may accumulate in large volumes (up to 500 to mL), usually the volume is small, and the pus becomes localized.

Empyema

Empyema may resolve, but this outcome is less common than organization of the exudate, with the formation of dense, tough fibrous adhesions that frequently obliterate the pleural space or envelop the lungs. This can seriously restrict pulmonary expansion. Resolution of inflammatory processes in body cavities may result in the formation of adhesions, which are thin bands of collagenous connective tissue, as seen here between the right lung and the chest wall at autopsy.

Hemorrhagic pleuritis manifested by sanguineous inflammatory exudates is found in hemorrhagic diatheses, rickettsial diseases, and neoplastic involvement of the pleural cavity. * When hemorrhagic pleuritis is encountered, careful search should be made for the presence of exfoliated tumor cells. The sanguineous exudate must be differentiated from hemothorax. Pleural effusion containing metastatic adenocarcinoma cells from a previously diagnosed lung carcinoma. A cluster of moderately atypical malignant cells with partly overlapping nuclei in routine preparation (HE, 320).

Noninflammatory Pleural Effusions
Chylothorax is an accumulation of milky fluid, usually of lymphatic origin, in the pleural cavity. Chyle is milky white because it contains finely emulsified fats. Chylothorax is most often caused by thoracic duct trauma or obstruction that secondarily causes rupture of major lymphatic ducts. It is encountered in malignant conditions arising within the thoracic cavity that cause obstruction of the major lymphatic ducts. More distant cancers may metastasize via the lymphatics and grow within the right lymphatic or thoracic duct to produce obstruction.

Pneumothorax Pneumothorax refers to air or gas in the pleural cavities and may be spontaneous, traumatic, or therapeutic.

Pleural Tumors The pleura may be involved by primary or secondary tumors. Secondary metastatic involvement is far more common than are primary tumors. The most frequent metastatic malignancies arise from primary neoplasms of the lung and breast.* In most metastatic involvements, a serous or serosanguineous effusion follows that often contains neoplastic cells. For this reason, careful cytologic examination of the sediment is of considerable diagnostic value. * In addition to these cancers, malignancy from any organ of the body may spread to the pleural spaces. Ovarian carcinomas, for example, tend to cause widespread implants in both the abdominal and thoracic cavities. Pleural effusion: Metastatic ductal carcinoma 60X

Solitary Fibrous Tumor
The tumor is often attached to the pleural surface by a pedicle. It may be small (1 to 2 cm in diameter) or may reach an enormous size, but it tends to remain confined to the surface of the lung. Grossly, it consists of dense fibrous tissue with occasional cysts filled with viscid fluid

Solitary Fibrous Tumor
Microscopically, the tumor shows whorls of reticulin and collagen fibers among which are interspersed spindle cells resembling fibroblasts. Rarely, this tumor may be malignant, with pleomorphism, mitotic activity, necrosis, and large size (>10 cm). The tumor cells are CD34+ and keratin- negative by immunostaining.* Unlike malignant mesotheliomas, the solitary fibrous tumor has no relationship to asbestos exposure. * This feature can be diagnostically useful in distinguishing these lesions from malignant mesotheliomas (which show the opposite phenotype).

Malignant Mesolthelioma
Asbestos bodies are found in increased numbers in the lungs of patients with mesothelioma. High-power detail of an asbestos body, revealing the typical beading and knobbed ends (arrow).

Malignant Mesolthelioma Morphology
Malignant mesothelioma is a diffuse lesion that spreads widely in the pleural space and is usually associated with extensive pleural effusion and direct invasion of thoracic structures. The affected lung becomes ensheathed by a thick layer of soft, gelatinous, grayish pink tumor tissue Malignant mesothelioma. Note the thick, firm, white pleural tumor tissue that ensheaths this bisected lung.

Microscopically, malignant mesotheliomas may be epithelioid (60%), sarcomatoid (20%), or mixed (20%). This is in keeping with the fact that mesothelial cells have the potential to develop as epithelium-like cells or mesenchymal stromal cells.

The epithelioid type of mesothelioma consists of cuboidal, columnar, or flattened cells forming tubular or papillary structures resembling adenocarcinoma.

Malignant mesothelioma, mixed type, stained for calretinin (immunoperoxidase method). The epithelial component is strongly positive (dark brown), while the sarcomatoid component is less so.

Chronic Diffuse Interstitial (Restrictive) Diseases
Chest radiographs show bilateral infiltrative lesions in the form of small nodules, irregular lines, or ground-glass shadows.

Fibrosing Diseases

Idiopathic Pulmonary Fibrosis Morphology
Grossly, the pleural surfaces of the lung are cobblestoned as a result of the retraction of scars along the interlobular septa. The cut surface shows fibrosis (firm, rubbery white areas) of the lung parenchyma with lower-lobe predominance and a distinctive distribution in the subpleural regions and along the interlobular septa. Gross photographs of UIP-associated lung. Honeycomb change along the periphery and lung bases (A). Prominent cobblestone appearance of the pleural surface (B).

Microscopically, the hallmark of UIP is patchy interstitial fibrosis, which varies in intensity and age. Usual interstitial pneumonia. The fibrosis is more pronounced in the subpleural region.

The earliest lesions contain exuberant fibroblastic proliferation (fibroblastic foci). With time these areas become more collagenous and less cellular. Typically both early and late lesions coexist about each other. Usual interstitial pneumonia. Fibroblastic focus (arrow) with fibers running parallel to surface and bluish myxoid extracellular matrix. Honeycombing is present on the left.

The dense fibrosis causes the destruction of alveolar architecture and formation of cystic spaces lined by hyperplastic type II pneumocytes or bronchiolar epithelium (honeycomb fibrosis).* There is mild to moderate inflammation within the fibrotic areas, consisting of mostly lymphocytes, and a few plasma cells, neutrophils, eosinophils, and mast cells. Pulmonary arterial hypertensive changes (intimal fibrosis and medial thickening) are often present. * With adequate sampling, these diagnostic histologic changes (i.e., areas of dense collagenous fibrosis with relatively normal lung and fibroblastic foci) can be identified even in advanced IPF. UIP with “honeycomb fibrosis”.

Coal Workers’ Pneumoconiosis Morphology
Anthracosis is the mildest coal- induced pulmonary lesion in coal miners and is also seen to some degree in urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the connective tissue along the lymphatics, including the pleural lymphatics, or in organized lymphoid tissue along the bronchi or in the lung hilus.

Simple CWP is characterized by coal macules (1 to 2 mm in diameter) and the somewhat larger coal nodules. The coal macule consists of carbon-laden macrophages; the nodule also contains small amounts of a delicate network of collagen fibers. They are located primarily adjacent to respiratory bronchioles, the site of initial dust accumulation. Eventually, dilation of adjacent alveoli occurs, a condition sometimes referred to as centrilobular emphysema.

Complicated CWP (progressive massive fibrosis) occurs on a background of simple CWP and generally requires many years to develop. It is characterized by intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter. They are usually multiple. Progressive massive fibrosis superimposed on coal workers’ pneumoconiosis. The large, blackened scars are located principally in the upper lobe. Note the extensions of scars into surrounding parenchyma and retraction of adjacent pleura.(Courtesy of Drs. Werner Laquer and Jerome Kleinerman, the National Institute of Occupational Safety and Health, Morgantown, WV.)

Microscopically the lesions consist of dense collagen and pigment. The center of the lesion is often necrotic, most likely due to local ischemia.

Silicosis Morphology Silicosis is characterized grossly in its early stages by tiny, barely palpable, discrete pale to blackened (if coal dust is also present) nodules in the upper zones of the lungs. As the disease progresses, these nodules may coalesce into hard, collagenous scars. Fibrotic lesions may also occur in the hilar lymph nodes and pleura. If the disease continues to progress, expansion and coalescence of lesions may produce progressive massive fibrosis. Advanced silicosis (transected lung). Scarring has contracted the upper lobe into a small dark mass (arrow). Note the dense pleural thickening. * Some nodules may undergo central softening and cavitation. This change may be due to superimposed tuberculosis or to ischemia.

Silicosis Morphology Histologic examination reveals that the nodular lesions consist of concentric layers of hyalinized collagen surrounded by a dense capsule of more condensed collagen. Examination of the nodules by polarized microscopy reveals the birefringent silica particles. Several coalescent collagenous silicotic nodules.

Silicosis Clinical Course
Earlier in the course, Chest radiographs typically show a fine nodularity in the upper zones of the lung, but pulmonary functions are either normal or only moderately affected. Silicosis features a diffuse micronodular lung disease with an upper lobe predominance.

Silicosis Clinical Course
Silicosis is associated with an increased susceptibility to tuberculosis. It is postulated that silicosis results in a depression of cell- mediated immunity, and crystalline silica may inhibit the ability of pulmonary macrophages to kill phagocytosed mycobacteria. Nodules of silicotuberculosis often display a central zone of caseation. Although the diagnosis of silicotuberculosis is made on the basis of clinical and radiographic assessment, the histologic correlate is central necrosis of the nodules. Granulomas typical of tuberculosis should not be expected. Here, in a conglomerate nodule stained for collagen (red), there is central necrosis, which suggests the diagnosis even if acid fast bacilli cannot be demonstrated histologically.

Asbestos-Related Diseases Morphology
Asbestosis is marked by diffuse pulmonary interstitial fibrosis, which is indistinguishable from diffuse interstitial fibrosis resulting from other causes, except for the presence of multiple asbestos bodies. These appear as golden brown, fusiform or beaded rods with a translucent center and consist of asbestos fibers coated with an iron-containing proteinaceous material.* * They arise when macrophages attempt to phagocytose asbestos fibers; the iron is presumably derived from phagocyte ferritin. (Also, Other inorganic particulates may become coated with similar iron-protein complexes and are called ferruginous bodies.)

Asbestosis begins as fibrosis around respiratory bronchioles and alveolar ducts and extends to involve adjacent alveolar sacs and alveoli. The fibrous tissue distorts the architecture, creating enlarged airspaces enclosed within thick fibrous walls; eventually the affected regions become honeycombed. The pattern of fibrosis is similar to that seen in UIP, with fibroblastic foci and varying degrees of fibrosis, the only difference being the presence of numerous asbestos bodies. Asbestosis

Pleural plaques, the most common manifestation of asbestos exposure, are well-circumscribed plaques of dense collagen, often containing calcium. They develop most frequently on the anterior and posterolateral aspects of the parietal pleura and over the domes of the diaphragm. They do not contain asbestos bodies. Asbestos-related pleural plaques. Large, discrete fibrocalcific plaques are seen on the pleural surface of the diaphragm.

Asbestos-Related Diseases Clinical Course
Chest x-rays reveal irregular linear densities, particularly in both lower lobes. With advancement of the pneumoconiosis, a honeycomb pattern develops.

Sarcoidosis Morphology
Histologically, all involved tissues show the classic well-formed noncaseating granulomas, each composed of an aggregate of tightly clustered epithelioid cells, often with Langhans or foreign body–type giant cells. Central necrosis is unusual. With chronicity the granulomas may become enclosed within fibrous rims or may eventually be replaced by hyaline fibrous scars. Laminated concretions composed of calcium and proteins known as Schaumann bodies and stellate inclusions known as asteroid bodies enclosed within giant cells are found in approximately 60% of the granulomas.* Though characteristic, these microscopic features are not pathognomonic of sarcoidosis, because asteroid and Schaumann bodies may be encountered in other granulomatous diseases (e.g., tuberculosis). Biopsy showing non-caseating granuloma formation characterized by epithelioid histiocytes, multinucleated giant cells and lymphocytes.

Sarcoidosis Morphology
Macroscopically, in the lungs there is usually no demonstrable alteration, although in advanced cases the coalescence of granulomas produces small nodules that are palpable or visible as 1 to 2 cm, noncaseating, noncavitated consolidations. Histologically, lung lesions are distributed primarily along the lymphatics, around bronchi and blood vessels, although alveolar lesions are also seen. The relative frequency of granulomas in the bronchial submucosa accounts for the high diagnostic yield of bronchoscopic biopsies. There is an apparent strong tendency for lesions to heal in the lungs, so varying stages of fibrosis and hyalinization are often found. Distribution of granulomas in pulmonary sarcoidosis. The granulomas are typically found in a lymphatic distribution, coursing along the pulmonary veins (upper arrow) and the airways (lower arrow). Image courtesy of Carol Farver, MD.

Hypersensitivity Pneumonitis Morphology
Histologic changes in subacute and chronic forms are characteristically centered on bronchiole, including: Interstitial pneumonitis consisting primarily of lymphocytes, plasma cells, and macrophages Noncaseating granulomas in two thirds of patients Interstitial fibrosis, honeycombing, and obliterative bronchiolitis (in late stages). In more than half the patients there is also evidence of an intra-alveolar infiltrate. Hypersensitivity pneumonitis, histologic appearance. Loosely formed interstitial granulomas and chronic inflammation are characteristic

PAP Morphology The disease is characterized by a peculiar homogeneous, granular precipitate within the alveoli, causing focal-to- confluent consolidation of large areas of the lungs with minimal inflammatory reaction. Axial CT of the chest shows extensive bilateral ground-glass opacities superimposed with interlobular septal thickening (arrows) in the upper, middle and lower lobes. There is no pleural effusion.

PAP Morphology The alveolar precipitate is periodic acid–Schiff positive and also contains cholesterol clefts. Pulmonary alveolar proteinosis, histologic appearance. The alveoli are filled with a dense, amorphous, protein-lipid granular precipitate, while the alveolar walls are normal.

Asthma Morphology In patients dying of status asthmaticus the lungs are overdistended because of overinflation, with small areas of atelectasis. The most striking macroscopic finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs. Plugging of the airways in fatal asthma. Gross view of a sliced lung specimen to show plugging of the airways in fatal asthma.

Asthma Morphology Histologically/cytologically, the mucus plugs contain whorls of shed epithelium, which give rise to the well-known spiral shaped mucus plugs called Curschmann spirals (These result either from mucus plugging in subepithelial mucous gland ducts which later become extruded, or from plugs in bronchioles). This very large spiral was found in lavage fluid from an asthmatic patient being evaluated for a lung mass. Many of these structures were present. The Papanicolaou stain gives a reddish core with a fuzzy margin to which many cells are attached secondarily. The arrow points out a macrophage for comparison of size. The spiral is about 1 mm long.

Asthma Morphology Also, Numerous eosinophils and Charcot-Leyden crystals are present on histology and/or cytology. The latter are collections of crystalloid made up of an eosinophil lyso-phospholipase binding protein called galectin- 10. Charcot-Leyden crystals in airway- Asthma Mucous and inflammatory exudate in the lumen of a bronchus with large Charcot-Leyden crystals.

Asthma Morphology The other characteristic histologic findings of asthma, collectively called “airway remodeling”, include: Overall thickening of airway wall Sub-basement membrane fibrosis Increased vascularity An increase in size of the submucosal glands and mucous metaplasia of airway epithelial cells Hypertrophy and/or hyperplasia of the bronchial wall muscle Bronchial biopsy specimen from an asthmatic patient showing sub-basement membrane fibrosis, eosinophilic inflammation, and muscle hyperplasia

Emphysema Morphology Advanced emphysema produces voluminous lungs, often overlapping the heart. Generally, the upper two thirds of the lungs are more severely affected.

Emphysema Morphology Large alveoli can easily be seen on the cut surface of formalin- inflated fixed lung Centriacinar emphysema. Central areas show marked emphysematous damage (E), surrounded by relatively spared alveolar spaces.

Emphysema Morphology Microscopically, there are abnormally large alveoli separated by thin septa with only focal centriacinar fibrosis. With advanced disease, there are even larger abnormal airspaces and possibly blebs or bullae, which often deform and compress the respiratory bronchioles and vasculature of the lung. Inflammatory changes in small airways are seen. Emphysema (left of image - large empty spaces) and lung tissue with relative preservation of the alveoli (right of image).

Chronic Bronchitis Morphology
Grossly, there is hyperemia, swelling, and edema of the mucous membranes, frequently accompanied by excessive mucinous or mucopurulent secretions. Sometimes, heavy casts of secretions and pus fill the bronchi and bronchioles.

Chronic Bronchitis Morphology
The characteristic histologic features are chronic inflammation of the airways (predominantly lymphocytes) and enlargement of the mucus-secreting glands of the trachea and bronchi. Although the numbers of goblet cells increase slightly, the major change is in the size of the mucous gland (hyperplasia). * *This increase can be assessed by the ratio of the thickness of the mucous gland layer to the thickness of the wall between the epithelium and the cartilage (Reid index). The Reid index (normally 0.4) is increased in chronic bronchitis, usually in proportion to the severity and duration of the disease

Acute Lung Injury and Acute Respiratory Distress Syndrome
The histologic manifestation of these diseases is diffuse alveolar damage (DAD). DAD

ARDS Morphology In the acute stage, the lungs are heavy, firm, red, and boggy. ARDS gross section of lung.

ARDS Morphology Histologically, they exhibit congestion, interstitial and intra-alveolar edema, inflammation, fibrin deposition, and diffuse alveolar damage. The alveolar walls become lined with waxy hyaline membranes. These membranes consist of fibrin-rich edema fluid mixed with the cytoplasmic and lipid remnants of necrotic epithelial cells. Diffuse alveolar damage (acute respiratory distress syndrome). Some of the alveoli are collapsed; others are distended, and many are lined by hyaline membranes (arrows).

ARDS Pathogenesis Hyaline membranes so characteristic of ALI/ARDS result from inspissation of protein rich edema fluid that entraps debris of dead alveolar epithelial cells. Diffuse alveolar damage (acute respiratory distress syndrome). Some of the alveoli are collapsed; others are distended, and many are lined by hyaline membranes (arrows).

ARDS Clinical Course Individuals who develop ALI are usually hospitalized for one of the predisposing conditions. Profound dyspnea and tachypnea herald ALI, followed by increasing cyanosis and hypoxemia, respiratory failure, and the appearance of diffuse bilateral infiltrates on radiographic examination. Hypoxemia can then become unresponsive to oxygen therapy, due to ventilation perfusion mismatching, and respiratory acidosis can develop.

Neonatal Respiratory Distress Syndrome
NRDS chest x-ray

Neonatal RDS Morphology
The lungs are distinctive on gross examination. Though of normal size, they are solid, airless, and reddish purple, similar to the color of the liver, and they usually sink in water.

Neonatal RDS Morphology
Microscopically, alveoli are poorly developed, and those that are present are collapsed. If the infant dies early in the course of the disease, necrotic cellular debris can be seen in the terminal bronchioles and alveolar ducts. The necrotic material becomes incorporated within eosinophilic hyaline membranes lining the respiratory bronchioles, alveolar ducts, and random alveoli. The membranes are largely made up of fibrin admixed with cell debris derived chiefly from necrotic type II pneumocytes. Hyaline membrane disease. There is alternating atelectasis and dilation of the alveoli. Note the eosinophilic thick hyaline membranes lining the dilated alveoli.

Cystic Fibrosis Morphology
Coronal sections of whole lungs and cross sections of small airways. Note the uniform parenchyma of normal lung (top left) in contrast to the lung from a cystic fibrosis (CF) patient (top right). The latter shows an enormous number of ectatic lesions (arrows) with most airways completely filled and obstructed with purulent mucoid accumulations (black arrows).

Bronchiectasis Etiology and Pathogenesis
Allergic bronchopulmonary aspergillosis is a condition that results from a hypersensitivity reaction to the fungus Aspergillus fumigatus. It is also an important complication of asthma and cystic fibrosis. Characteristics are high serum IgE levels, serum antibodies to Aspergillus, intense airway inflammation with eosinophils, and the formation of mucus plugs, which play a primary role in its pathogenesis. There is evidence that neutrophil-mediated inflammation and a relative deficiency of anti- inflammatory cytokines such as IL-10 may also play a role. Clinically, there are periods of exacerbation and remission that may lead to proximal bronchiectasis and fibrotic lung disease.

Bronchiectasis Morphology
The airways are dilated, sometimes up to four times normal size. Characteristically, the bronchi and bronchioles are sufficiently dilated that they can be followed almost to the pleural surfaces (By contrast, in the normal lung, the bronchioles cannot be followed by ordinary gross dissection beyond a point 2 to 3 cm from the pleural surfaces). On the cut surface of the lung, the transected dilated bronchi appear as cysts filled with mucopurulent secretions

Bronchiectasis Morphology
The histologic findings vary with the activity and chronicity of the disease. In the full-blown, active case there is an intense acute and chronic inflammatory exudation within the walls of the bronchi and bronchioles, associated with desquamation of the lining epithelium and extensive areas of necrotizing ulceration. In some instances the necrosis completely destroys the bronchial or bronchiolar walls and forms a lung abscess. Fibrosis of the bronchial and bronchiolar walls and peribronchiolar fibrosis develop in the more chronic cases, leading to varying degrees of subtotal or total obliteration of bronchiolar lumens. A subsegmental bronchus from a patient with bronchiectasis.

Carcinomas of the Lung Morphology
Precursor lesions of squamous cell carcinomas. Some of the earliest (and “mild”) changes in smoking-damaged respiratory epithelium include goblet cell hyperplasia (A), basal cell (or reserve cell) hyperplasia (B), and squamous metaplasia (C). More ominous changes include the appearance of squamous dysplasia (D), characterized by the presence of disordered squamous epithelium, with loss of nuclear polarity, nuclear hyperchromasia, pleomorphism, and mitotic figures. Squamous dysplasia may, in turn, progress through the stages of mild, moderate, and severe dysplasia. Carcinoma-in-situ (CIS) (E) is the stage that immediately precedes invasive squamous carcinoma (F), and apart from the lack of basement membrane disruption in CIS, the cytologic features are similar to those in frank carcinoma. Unless treated, CIS will eventually progress to invasive cancer.

Lung carcinoma. The gray-white tumor tissue is seen infiltrating the lung substance. Histologically, this large tumor mass was identified as a squamous cell carcinoma.

Often carcinomas erode the bronchial epithelium and can be diagnosed by cytologic examination of sputum, bronchoalveolar lavage fluid, or fine-needle aspiration. Cytologic diagnosis of lung cancer. A sputum specimen shows an orange-staining, keratinized squamous carcinoma cell with a prominent hyperchromatic nucleus (arrow). Note the size of the tumor cells compared with normal polymorphonuclear leukocytes in the left lower corner.

Adenocarcinoma of the Lung Morphology
Adenocarcinoma is the most common type of lung cancer in women and nonsmokers*. As compared with squamous cell cancers, the lesions are usually more peripherally located, and tend to be smaller. Adenocarcinoma lung. * Adenocarcinomas, including bronchioloalveolar carcinomas, are less frequently associated with a history of smoking (still, greater than 75% are found in smokers) than are squamous or small cell carcinomas (>98% in smokers).

Adenocarcinoma of the Lung Morphology
Adenocarcinomas 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. The majority are positive for thyroid transcription factor-1 (TTF-1) on immunoperoxidase study. About 80% of tumors contain mucin. Adenocarcinomas grow more slowly than squamous cell carcinomas but tend to metastasize widely and earlier. Gland-forming adenocarcinoma, inset shows thyroid transcription factor 1 (TTF-1) positivity.

Bronchioalveolar Carcinoma Morphology
As the name implies, bronchioloalveolar carcinoma occurs in the pulmonary parenchyma in the terminal bronchioloalveolar regions. It represents, in various series, 1% to 9% of all lung cancers. Macroscopically, the tumor almost always occurs in the peripheral portions of the lung either as a single nodule or, more often, as multiple diffuse nodules that sometimes coalesce to produce a pneumonia-like consolidation. The parenchymal nodules have a mucinous, gray translucence when secretion is present but otherwise appear as solid, gray-white areas that can be confused with pneumonia on gross inspection. Bronchioloalveolar carcinoma, cut section.

Bronchioalveolar Carcinoma Morphology
Histologically, BAC is characterized by a pure bronchioloalveolar growth pattern with no evidence of stromal, vascular, or pleural invasion. The key feature of bronchioloalveolar carcinomas is their growth along preexisting structures without destruction of alveolar architecture (This growth pattern has been termed lepidic). Ultrastructurally, BACs are a heterogeneous group, consisting of mucin-secreting bronchiolar cells, Clara cells, or, rarely, type II pneumocytes. Bronchioloalveolar carcinoma, mucinous subtype, with characteristic growth along pre-existing alveolar septa, without invasion.

Two Subtypes of Bronchioalveolar Carcinoma
Nonmucinous BAC, with columnar, peg- shaped, or cuboidal cells. Mucinous BAC, with distinctive, tall, columnar cells with cytoplasmic and intra-alveolar mucin, growing along the alveolar septa.

Squamous Cell Carcinoma SCCA 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.* These features are prominent in the well- differentiated tumors, are easily seen but not extensive in moderately differentiated tumors, and are focally seen in poorly differentiated tumors. In the past, most squamous cell carcinomas were seen to arise centrally from the segmental or subsegmental bronchi. However, the incidence of squamous cell carcinoma of the peripheral lung is increasing. * Keratinization may take the form of squamous pearls or individual cells with markedly eosinophilic dense cytoplasm.

SCCA Morphology SCCA with intercellular bridges

Small Cell Carcinoma This highly malignant tumor has a distinctive cell type: The epithelial cells are relatively small, with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin (salt and pepper pattern), and absent or inconspicuous nucleoli . The cells are round, oval, or spindle-shaped, and nuclear molding is prominent. There is no absolute size for the tumor cells, but in general they are smaller than three small resting lymphocytes. The mitotic count is high. The cells grow in clusters that exhibit neither glandular nor squamous organization. Necrosis is common and often extensive. Small cell carcinoma with islands of small deeply basophilic cells and areas of necrosis.

Large Cell Carcinoma This is an undifferentiated malignant epithelial tumor that lacks the cytologic features of small-cell carcinoma and glandular or squamous differentiation. The cells typically have large nuclei, prominent nucleoli, and a moderate amount of cytoplasm. Large cell carcinomas probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they can no longer be recognized by light microscopy. Ultrastructurally, however, minimal glandular or squamous differentiation is common. Large cell carcinoma, featuring pleomorphic, anaplastic tumor cells with no squamous or glandular differentiation.

Large Cell Carcinoma One histologic variant is large cell neuroendocrine carcinoma. This is recognized by such features as organoid nesting, trabecular, rosette-like, and palisading patterns. These features suggest neuroendocrine differentiation, which can be confirmed by immunohistochemistry or electron microscopy. Large cell neuroendocrine carcinoma.

Neuroendocrine Proliferations and Tumors
The normal lung contains neuroendocrine cells within the epithelium as single cells or as clusters, the neuroepithelial bodies. Normal pulmonary NECs: In normal, adult human lungs, pulmonary NECs react with antibodies to chromogranin A, gastrin releasing peptide, calcitonin, and protein gene product 9.5, but are best demonstrated with antibodies to chromogranin A, as shown in the photo (two brown-stained cells). In adults, PNECs normally occur as single cells.

Carcinoid Tumors Morphology
Carcinoids may arise centrally or may be peripheral. On gross examination, the central tumors grow as finger-like or spherical polypoid masses that commonly project into the lumen of the bronchus and are usually covered by an intact mucosa.* They rarely exceed 3 to 4 cm in diameter. Most are confined to the main stem bronchi. Peripheral tumors are solid and nodular. A. Bronchial carcinoid. Carcinoid growing as a spherical, pale mass (arrow) protruding into the lumen of the bronchus. Others produce little intraluminal mass but instead penetrate the bronchial wall to fan out in the peribronchial tissue.

Histologically, the tumor is composed of organoid, trabecular, palisading, ribbon, or rosette-like arrangements of cells separated by a delicate fibrovascular stroma. Similar to carcinoids of the gastrointestinal tract, the individual cells are quite regular and have uniform round nuclei and a moderate amount of eosinophilic cytoplasm. B, Histologic appearance, demonstrating small, rounded, uniform nuclei and moderate cytoplasm

Typical carcinoids have fewer than two mitoses per ten high- power fields and lack necrosis, while atypical carcinoids have between two and ten mitoses per ten high-power fields and/or foci of necrosis. Atypical carcinoids also show increased pleomorphism, have more prominent nucleoli, and are more likely to grow in a disorganized fashion and invade lymphatics. Atypical carcinoid, with mitoses (arrows). Features include recognized carcinoid pattern with increased mitoses, nuclear pleomorphism, prominent nucleoli, increased cellularity, disorganized architecture and small areas of necrosis (left of photo).

Miscellaneous Tumors A lung hamartoma is a relatively common lesion that is usually discovered as an incidental, rounded focus of radio-opacity (coin lesion) on a routine chest film. The majority of these tumors are peripheral, solitary, less than 3 to 4 cm in diameter, and well circumscribed. Pulmonary hamartoma consists of nodules of connective tissue intersected by epithelial clefts. Cartilage is the most common connective tissue, but there may also be cellular fibrous tissue and fat. The epithelial clefts are lined by ciliated columnar epithelium or nonciliated epithelium and probably represent entrapment of respiratory epithelium. Pulmonary hamartoma. There are islands of cartilage and entrapped respiratory epithelium.

Metastatic Tumors Morphology
The pattern of metastatic growth within the lungs is variable. In the usual case, multiple discrete nodules (cannonball lesions) are scattered throughout all lobes, more being at the periphery. Other patterns include solitary nodule, endobronchial, pleural, pneumonic consolidation, and mixtures of the above. Foci of lepidic growth similar to bronchioloalveolar carcinoma are seen occasionally with metastatic carcinomas. Numerous metastases to lung from a renal cell carcinoma.

Pulmonary Embolism Morphology

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Pulmonary Embolism Morphology

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