Editors: Mills, Stacey E.
Title: Histology for Pathologists, 3rd Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > VI - Thorax and Serous Membranes > 18 - Lungs
Thomas V. Colby
Kevin O. Leslie
Samuel A. Yousem
Normal Structure and Histology
The following review is based on several standard references on the topic ( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ).
The lungs are paired intrathoracic organs that are divided into lobes (three on the right ”right upper lobe, right middle lobe, right lower lobe; two on the left ”left upper lobe, left lower lobe). The lingula is a rudimentary appendage arising from the left upper lobe and is analogous to the middle lobe on the right. The
The segmental anatomy of the lung is important for radiologists, bronchoscopists, and pathologists in defining the location of lesions. The lobes are divided by fissures and have their own pleural investments. The segments are not separated by fissures and do not normally have separate pleural investments, although they are recognizable on the basis of their supplying bronchi (segmental bronchi).
The primordial lungs arise as ventral buds of the foregut extending into the primitive thoracic mesenchyme. Bronchial cartilages, smooth muscle, and other connective tissues are derived from the mesenchyme that
As the lung progresses through these phases of development, there is a complex series of epithelial-mesenchymal
factors ( 17 , 18 ). Some of these mediators and their relationship to lung development are shown in Table 18.3 .
Table 18.1 Bronchopulmonary Segments *
Table 18.2 Phases of Lung Development
Table 18.3 Lung Development and Regulatory Factors *
The airways serve as
The airways arise by
Bronchi are cartilaginous airways and are usually more than 1 mm in diameter ( Figure 18.1 ). They are conducting airways, and the cartilage plates in their walls prevent their collapse. The posterior wall is smooth muscle. The cartilage may calcify.
Figure 18.1 Bronchus. Alcian blue staining of the bronchus highlights the presence of goblet
cellsin the mucosa (slightly increased in this case), as well as the bronchial submucosalglands. Beneaththe epithelial basement membrane, there is a vascularized layer of connective tissuewith wisps of smooth muscle above the submucosal glands.
Bronchioles are airways that are usually less than 1 mm in diameter; they lack cartilage ( Figure 18.2 ).
Nonrespiratory bronchioles represent all bronchioles proximal to respiratory bronchioles.
Terminal bronchioles are nonrespiratory bronchioles just proximal to respiratory bronchioles.
Respiratory bronchioles are airways that have alveoli budding from their walls.
In the large bronchi, the surface epithelium rests on a basement membrane, below which there is an elastin-rich layer of connective tissue; together these elements comprise the
. Beneath the bronchial mucosa lies the
in which submucosal glands, cartilage, nerves, ganglia, and branches of the bronchial artery may be found. There is no clear histologic boundary between mucosa and submucosa. Outside the submucosa, there is a peribronchial sheath of loose connective tissue, which is continuous with that of the accompanying artery. The bronchial epithelium is a pseudostratified
The height of the pseudostratified columnar epithelium decreases progressively toward the periphery of the lung.
Bronchioles. Hematoxylin and eosin (
) and elastic tissue stains (
These canals represent communications between nonrespiratory bronchioles and adjacent alveoli and are only rarely
The walls of bronchioles are normally much thinner than those of the bronchi. The surface epithelium rests on a basement membrane, which overlies a thin layer of loose elastin-rich connective tissue. This is surrounded by a muscle layer (muscularis), which is in
The airway basement membrane region consists of three
Direct communications between nonrespiratory bronchioles and alveoli have been identified and termed Lambert's canals (
). These are thought to be involved in
Smooth muscle of the airways plays an important functional role in regulating airflow and is arranged in a complex spiral pattern that becomes progressively less prominent in the distal conducting airways. This muscle receives nutrition from the bronchial arteries. At the level of the alveolar ducts, bundles of airway smooth muscle can be seen,
Submucosal salivary-type glands containing both serous and mucous cells are found in the larger bronchi. In older individuals, oncocytic metaplasia can be seen in these glands ( Figure 18.7 ). Within the walls of the large airways, ganglia, nerves, and bronchial arteries are found.
Figure 18.4 Respiratory tract epithelia. There is a progression of pseudostratified columnar epithelium in the large airways, to a more cuboidal epithelium in the small airways, to squamous type epithelial cells (type I pneumocytes) in the alveoli. The epithelium in the large airways is designed for maintaining and moving the mucous stream, whereas the squamous pneumocytes in the airspaces facilitate gas transfer. (Reprinted with permission from:
Weibel ER, Taylor CR. Design and structure of the human lung. In: Fishman AP, ed. Pulmonary Diseases and Disorders . Vol 1. 2nd ed. New York: McGraw-Hill; 1988:14.)
Normal bronchial epithelium is pseudostratified and columnar, with
Sorokin SP. The respiratory system. In: Weiss L, ed. Cell and Tissue Biology: A Textbook of Histology . 6th ed. Baltimore: Williams & Wilkins; 1988:769.)
Table 18.4 Major Cell Types of the Lower Respiratory Tract *
Clara cells. Although Clara cells sometimes can be identified in bronchioles, these are seen to best advantage in neoplasms such as this nonmucinous bronchioloalveolar
Lobule and Acinus
The lung lobule is grossly visible and represents the smallest anatomic subunit of the lung that is bounded by connective tissue (interlobular) septa, which may appear to invaginate from the visceral
Figure 18.7 Bronchial submucosal glands. A. The bronchial submucosal glands are normally located in the submucosa above the bronchial cartilage and contain mixed seromucous glands with a duct leading to the bronchial mucosa (also Figure 18.1 ). B. Oncocytic metaplasia involving bronchial submucosal glands is relatively common.
Pulmonary lobule. This cut section of normal lung tissue (from an explant that could not be used for technical reasons) shows focal hemorrhage highlighting a pulmonary lobule. The hemorrhage stops abruptly at the interlobular septa and,
The functional unit of the lung is the acinus, where gas transfer takes place ( Figure 18.9 ). The precise definition of the acinus has varied. Some define it as the lung tissue supplied by a single terminal bronchiole ( 12 , 15 ). According to this definition, each pulmonary lobule comprises some 3 to 10 acini. The acinus has also been defined as a respiratory bronchiole and its supplied alveolar ducts and sacs ( 10 , 13 ); using this definition, each lobule comprises some 20 to 30 acini and the acini are 1 to 2 mm in diameter.
Squamous (type I pneumocytes) and cuboidal (type II, or granular, pneumocytes) epithelial cells line the alveoli ( Table 18.4 ). Gas exchange takes place across the cytoplasm of type I cells. Type II cells are the progenitors for type I cells, produce surfactant, and proliferate after injury to restore alveolar epithelial integrity. Type II cell hyperplasia represents a nonspecific marker of alveolar injury and repair ( Fig 18.10 ). Macrophages are a normal finding in the lung, scattered over the surfaces of the alveoli and percolating into the interstitium; a number of subpopulations of pulmonary macrophages are definable, based on their anatomic locations and their role in host defense clearance functions ( 31 ). Pulmonary macrophages are greatly increased in cigarette smokers; increased Langerhans cells are also found in the
bronchiolar epithelium of smokers, but their recognition requires special stains (e.g., CD1a) and quantitative studies.
Distal lung parenchyma. The acinus is the functional unit of the lung where a gas transfer takes place.
An alveolar duct extends from the left to right and communicates directly with alveolar spaces; a small interlobular septum (
) and the pleura (
) are present. (From the case illustrated in
The epithelial and capillary basement membranes in the alveolar septum are irregularly fused. Gas transfer takes place across the alveolar-capillary membrane, which includes the attenuated cytoplasm of the type I cell, the endothelial cell cytoplasm, and their fused basement membranes. Pores of Kohn represent direct communications between adjacent alveoli via a pore in the alveolar wall. They are thought to be involved in collateral ventilation. Pores of Kohn are rarely visible with the light microscope.
The lung is invested with a rich framework of connective tissue coursing throughout the interstitium. It is well developed and easily visible along bronchovascular sheaths and in the septa that
Alveolar cell hyperplasia. A reactive
Given the concentration of nuclei of the various cell types comprising the alveolar wall, it may be difficult to decide when some degree of cellularity is pathologic. Although one may attempt to count nuclei in a single alveolar wall, it is more practical to assess inflammatory cell infiltrates in the perivenular
The lungs have
membrane ( Fig. 18.11A ); pulmonary veins have only a lamellated single (outer) elastica ( Fig. 18.11B ). Small intra-acinar pulmonary veins merge into larger veins in the interlobular septa. The bronchial arteries in the walls of bronchi are part of the systemic circulation and have pressures similar to systemic arterial pressures. The pulmonary circulation is a low pressure system with a normal mean pressure of approximately 10 mmHg (it is somewhat higher at higher
Figure 18.11 Pulmonary vasculature (elastic stains). Normal pulmonary arteries contain two elastic lamina ( A ), whereas veins have a single elastic lamina ( B ). The location of a vein within a septum (B) is also very helpful in identifying it as a vein.
It may be difficult to separate small pulmonary arterioles from venules,
Lymphatics and Lymphoid Tissue
The lung is invested with a rich supply of lymphatics and lymphoid tissue. Lymphatic drainage is toward the hilum of the lung. Lymph fluid from the lower lobes tends to drain to infratracheal lymph nodes, with lymph fluid from the remaining portions of the lung draining to tracheobronchial lymph nodes. On the left side, the lymph fluid drains into the thoracic duct; and, on the right side, it drains into the right bronchomediastinal trunk. Both of these ultimately drain into the left and right subclavian veins, respectively. Lymphatic channels are found along bronchovascular structures and pulmonary veins and in the septa and pleura. Valves may be apparent in some sections. Lymphatics do not extend into alveolar walls. The lymphatics vessels are inconspicuous except in pathologic states, such as pulmonary edema or lymphangitic carcinoma. Lymphoreticular infiltrates and some pneumoconioses tend to be distributed along the lymphatic routes, but the lymphatic vessels
Lymphoid tissue may be seen as small collections of lymphocytes along the lymphatic routes, especially branch points of the bronchovascular bundles; lymphoid tissue is
Immunophenotypically the lymphoid tissue of BALT has an immunoarchitecture with four identifiable compartments, including B-cell “rich follicles, B-cell follicular mantle and marginal zones, and T-cell “rich interfollicular regions. A follicular dendritic cell network is present. Polyclonal plasma cells are identified in the perifollicular tissue. The finer details of the immunoarchitecture and the
immunophenotypic characterization of these cells are beyond the scope of this review. The follicles tend to be polarized into a
As currently defined, BALT refers only to lymphoid tissue along the airways ( 35 ) and not to the lymphoid tissue that may be seen in the pleura and septa as part of diffuse lymphoid hyperplasia in the lung. Hyperplasia of BALT is frequently accompanied by lymphoid hyperplasia at these other sites.
Intrapulmonary peribronchial lymph nodes are a normal finding, but peripheral intraparenchymal lymph nodes are less common; however, in smokers and others with high dust exposure, they are increasingly recognized (and biopsied) with current imaging techniques ( 36 ). Intrapulmonary lymph nodes are usually septal or subpleural in location (see below). Anthracosis and small amounts of silica and silicates in these nodes is common and nonspecific.
The visceral pleura is composed of connective tissue, elastic tissue, and an outer mesothelial layer (
). The elastic tissue is often not a single layer, and several layers may be apparent. In pathologic conditions the elastic tissue may greatly increase. Elastic tissue stains are useful in assessing whether a given pathologic process, such as carcinoma, has transgressed the visceral pleura (
), but interpretation is difficult when the pleura is fibrotic and the elastic tissue is increased. Pleural assessment is important in separating T1 carcinomas from T2 carcinomas; the latter invade the visceral pleura (
). Lymphatic vessels that are continuous with those in the interlobular septa are also identifiable in the pleura. When the pleura is fibrotic and in foci of pleural adhesions, vessels may be thick and sclerotic or even pseudoangiomatous in appearance. Fatty metaplasia is often striking in foci of pleural and subpleural scarring. The visceral pleura often remains
Pleural elastic tissue (elastic stains). The pleura contains an elastic tissue membrane, which may appear as a single thin layer of elastic tissue (
) or as a richer network with
Special Stains and the Evaluation of Lung Histology
While most diagnostic work in lung histology and pathology can be performed with routine hematoxylin-eosin (H&E) staining , there are a number of special stains that aid interpretation and or highlight findings. Elastic tissue staining is helpful in evaluating the pulmonary vasculature, airways, and pleura. Sometimes arteries and veins can be distinguished from each other with elastic tissue staining. Elastic tissue staining highlights damage to the intima and media that might not be apparent on H&E staining. Elastic
tissue stains are also useful in highlighting abnormalities of bronchioles and may confirm the bronchiolar or alveolar duct origin of small scars in cases of complete obliteration of the small airways. Elastic tissue staining is helpful in highlighting the pleural elastica and its relationship to tumors.
Trichrome staining (or other stains highlighting connective tissues) may also be useful in highlighting normal and pathologic findings in the lung, but they do not provide quite as much information as elastic tissue stains. Trichrome staining may be useful in assessing the distribution and extent of fibrosis in fibrosing diseases. Reticulin stains and stains for collagen type IV may be used to highlight the reticulin network of the lung. This staining may be useful in research studies and in highlighting normal histology but is not generally useful in diagnostic surgical pathology of the lung.
Immunostains for epithelial markers (such as EMA and cytokeratin stains) may be beneficial in atelectatic or fibrotic lung when it is difficult to appreciate the architectural features on H&E staining. Comparing these stains with stains for endothelial cells (such as CD31 or CD34) may provide an additional aid in assessing lung architecture and structural relationships. Use of CD31 may be somewhat confusing since alveolar macrophages frequently show prominent staining. Lymphoid tissue in the lung is assessed with the panoply of lymphoid markers used at other sites. Both CD3 and CD20 are often useful to check the proportion and distribution of T and B cells, respectively. In general, most inflammatory conditions have a preponderance of T cells as the diffuse component of the infiltrates, with scattered B-cell follicles. In lymphoproliferative conditions, cytokeratin staining highlights lymphoepithelial lesions. Both S-100 and CD1a are useful in identifying Langerhans cells; the latter stain is much more specific.
Mesothelial cells lining the pleura typically stain with calretinin, cytokeratin 5/6, and WT-1 (nuclear positivity).
Pattern Recognition Based on Normal Anatomic Landmarks
It is useful to define pathologic conditions in the lung in relation to normal anatomic landmarks ( Figure 18.13 ). This can usually be done with diffuse diseases and often with localized processes. Such an exercise in diffuse lung disease is extremely useful in correlation with gross findings, as well as with high-resolution computed tomography (HRCT) scanning ( 38 ). Histologic patterns and their corresponding HRCT patterns can be recognized and are shown in Table 18.5 .
It is apparent that there is close correlation (but not a 1:1 relationship) between histology and HRCT. With some communication between the pathologist and the radiologist, there is a significant mutual
Table 18.5 * Corresponding Histologic and Radiologic Patterns
Site specific changes that may be primary lesions or incidental findings in surgical material are shown in Table 18.6 .
Biopsies from lobar tips, particularly from the lingula or right middle lobe, may show incidental inflammatory and fibrotic changes ( 39 ), including interstitial fibrosis, epithelial metaplasia, and even focal honeycombing ”all of which may not be representative of a diffuse process. Myointimal proliferation is common in the arteries and veins of these biopsies. The airspaces may contain aggregates of macrophages and neutrophils. Because of their accessibility, these sites are often biopsied. Incidental changes in lobar tips are usually obvious as such, since the more proximal lung tissue is either not affected or significantly less affected. Thus, in evaluation of lobar tip wedge biopsies, the findings of greatest significance are often in the more proximal portions of the specimen. Nonspecific inflammatory changes in lobar tips become a problem in small wedge biopsies, particularly those that are 2 cm or less in greatest dimension. Since lobar tips are so readily accessible to the surgeon, it is difficult to discourage surgeons from biopsying them. If possible, such biopsies should be at least 3.0 cm in greatest dimension. The possibility of middle lobe syndrome (which may affect the lingula, the right middle lobe, or both) ( 40 , 41 ) should be considered for persistent infiltrates in these sites.
Table 18.6 Site-Specific Changes in Lung Tissue
Apical caps (
) were once thought to be the result of healed tuberculosis, but they are common in
are rich in thickened elastic fibers; the background structure of
Figure 18.14 Apical cap. A. Apical caps are found at the apex of the upper lobe, as well as the apex of the lower lobe. They represent regions of pleural and subpleural thickening by elastotic fibrous tissue that may be grayish or eosinophilic in appearance. B. Higher power sometimes shows a rich elastic tissue network that appears to highlight alveolar wall structure; some anthracotic pigmented is also noted.
Figure 18.15 Subpleural emphysematous change in smoking. A. There is simplification of airspaces. B. Some of the alveolar walls show mild fibrosis with hyaline appearing collagen. Occasional clusters of pigmented alveolar macrophages are also noted.
Centriacinar (centrilobular) emphysema is a pathologic abnormality that is more common and more severe in the upper lobes (
); it is found predominantly in cigarette smokers and is a common finding in lobes resected for bronchogenic carcinoma. Emphysematous changes are frequently accompanied by some degree of fibrosis, particularly when bullous change is present. The fibrosis tends to appear as strands of dense, hypocellular, brightly eosinophilic collagenous septa traversing the emphysematous spaces. Anthracosis is also a common finding in smokers and urban dwellers. Focal pleural and subpleural fibrosis (
) is extremely common, especially as an incidental microscopic finding in lobar resections from smokers (
); abnormal airspaces
Figure 18.16 Pneumothorax. A. So-called subpleural blebs are thought to predispose to pneumothorax. These are regions of pleural and subpleural scarring with abnormal airspaces somewhat reminiscent to smoking-related changes (also Figure 18.15 ). B. Pneumothorax is often associated with a pleural reaction ( top ), which has been labeled eosinophilic pleuritis because of the association of eosinophil infiltrate and mesothelial and macrophage reaction on the pleural surface.
Subpleural blebs ( Figure 18.16 ) are often the only pathologic change found in patients with recurrent pneumothoraces and who don't have diffuse lung disease ( 47 ). These are typically evident in the upper lobes. By convention, blebs are defined as being less than 1.0 cm in diameter and some are derived from air dissection into the visceral pleura; bullae are 1.0 cm or greater in diameter ( 48 ).
Adhesions between the pleura and chest wall are composed of fibrovascular tissue with pockets of
Artifacts Seen in Lung Biopsy and Resection Material
Artifacts related to lung biopsy of prior procedures are described in Table 18.7 .
Knowledge of the clinical course of events prior to lung biopsy usually allows the pathologist to avoid
Table 18.7 Artifacts Seen in Lung Biopsies and Resections
Figure 18.17 Needle tract to a small peripheral adenocarcinoma. The biopsy had been performed a week earlier, and the needle tract shows evidence of hemorrhage, necrosis, organization, and epithelial regeneration.
Ventilator-associated changes. Common changes in the setting of positive-pressure ventilator
This fragment from a transbronchial biopsy shows compression and atelectasis (
) with some recognizable alveolar walls (
). The rounded spaces represent bubble artifact, which is common in such compressed biopsies.
Sponge artifact is illustrated. Note the marked irregularity of the space corresponding to the irregular surface of
Compression of the lung tissue, particularly in transbronchial biopsies, may produce rounded spaces in alveoli that resemble fat vacuoles and can easily be mistaken for exogenous lipoid pneumonia ( Figure 18.19 ). This artifactual change, often called bubble artifact ( 54 , 55 ), can be recognized because there are no macrophages or giant cells with small intracytoplasmic lipid vacuoles (all the vacuoles are extracellular), and there is usually little fibrosis, which is a constant feature of chronic exogenous lipoid pneumonia.
Compression of airways produces crinkling and
Compression-induced nuclear smearing artifact can be produced in any cellular tumor and even in reactive lymphoid tissue in the bronchial mucosa or biopsies of hilar or mediastinal nodes. The resulting changes may suggest small cell carcinoma. Reactive lymphoid follicles, lymphomas, and carcinoid tumors may be extremely difficult to distinguish from small cell carcinoma when this phenomenon is present. Recognition of these diagnostic pitfalls, examining multiple levels (especially at the periphery), and enlisting the aid of concomitant cytology specimens and immunohistochemistry allows resolution of most cases. In rare instances, rebiopsy may be necessary.
Atelectasis may be encountered in all types of lung biopsies since lung tissue is soft and readily
are endothelial or epithelial in origin, rather than inflammatory. Leukocyte common antigen immunostaining and immunohistochemical stains for other lymphoid markers may be useful in this setting. It is also unusual in
Figure 18.20 Atelectasis. Careful examination shows that recognizable alveolar walls can be traced into the region of atelectasis ( lower right ) and that the process stops somewhat abruptly at an interlobular septum that courses diagonally across the field ( lower left to upper right ).
Traumatic hemorrhage. The right side of the field shows
Fresh intra-alveolar hemorrhage due to the trauma of surgery is extremely common in biopsy material and should not be overinterpreted as pathologic (
). In fact, hemorrhage related to the trauma of the procedure is the most common cause of fresh blood in alveolar spaces. One can approach this problem from three points of view: the statistical, the histologic, and the clinical. Statistically, the vast majority of cases of fresh alveolar hemorrhage are traumatic since pathologic alveolar hemorrhage is relatively uncommon; thus, in any given case, acute hemorrhage is
The most common cause of macrophages staining positively with iron stains is respiratory bronchiolitis in smokers ( Figure 18.22 ). The hemosiderin in smoker's macrophages is finely granular, in contrast to the coarse, dark blue staining in chronic hemorrhage as highlighted by the Prussian blue histochemical stain for iron. Nevertheless, it is surprising how many darkly staining Prussian blue “positive cells can be seen in smokers.
Finally, the clinician can usually confirm whether an alveolar hemorrhage syndrome or alveolar hemorrhage due to some other cause (e.g.,
Prolonged surgical manipulation of the lung, and even multiple transbronchial biopsies, can lead to margination of neutrophils in capillaries (especially those in the pleura), which mimics capillaritis ( 56 ). Capillaritis is usually associated with some evidence of an alveolar hemorrhage syndrome or other clinical or histologic features of a vasculitic syndrome (such as vascular necrosis, karyorrhexis, and fibrin thrombi). It is distributed throughout a biopsy and is not limited to those regions manipulated during surgery. Clamping of the biopsy specimen prior to removal can result in lymphatic obstruction, dilatation, and septal edema.
Lung pathologists are divided on the issue of inflation fixation of biopsy specimens. This can be easily accomplished with a syringe filled with formalin and a fine gauge needle. Careful inflation of a lung biopsy specimen ( 57 ) may be helpful diagnostically and is aesthetically pleasing since the lung architecture is more easily appreciated (and particularly amenable to photography). A heavy hand can create overdistension of the alveoli and an emphysematous appearance. If this occurs, clinical correlation may be required to assess whether emphysema is actually a clinical consideration. Patchy atelectatic (uninflated) portions of lung tissue are common in biopsies that have been nonuniformly inflated. One problem that may be encountered in inflated biopsies is that cells and fluid may be washed out of the airspaces. This is especially true of smoker's (respiratory) bronchiolitis, which may be quite subtle in inflated specimens. A practical compromise to the issue of whether or not to inflate wedge biopsies was proposed by Dr. Lewis Woolner at the Mayo Clinic several decades ago (personal communication). One takes a wedge biopsy (even specimens from which tissue has been taken for studies such as frozen section) and simply places it in a closed container of formalin and shakes it up for a few seconds. This simple procedure allows the tissue to inflate somewhat on its own and the resultant histologic sections are remarkably good.
Video-assisted thoracic surgical (VATS) lung biopsies (thoracoscopic biopsies) have largely
fact that bimanual palpation is not as
Respiratory bronchiolitis. A respiratory bronchiole (
) shows an accumulation of pigmented macrophages in the lung with slight associated interstitial widening. The macrophages have a
Plastic sponges are often put in cassettes to ensure that small specimens are not lost during processing. Sponge artifact, with
Incidental Findings in Lung Biopsy and Resection Tissue
There are a number of incidental findings in lung tissue that may not be related to the primary process that prompted the biopsy or resection ( Table 18.8 ). Sometimes these incidental findings are of clinical and pathologic significance, and other times they are of no significance. Correlation of the individual finding(s) with the clinical and radiologic presentation helps to determine their significance.
Findings related to smoking and emphysema are extremely common, especially in lungs resected for bronchogenic carcinoma ( 46 ). They may be divided into three broad groups: large airway changes, small airway lesions, and abnormalities of the alveolar parenchyma.
In the large airways, one sees goblet cell hyperplasia, squamous metaplasia (with or without dysplasia), basement membrane thickening, hypertrophy and hyperplasia of bronchial glands with dilated ducts and mucostasis, and, often, a mild submucosal chronic inflammatory infiltrate ( 45 , 48 ).
The changes in the small airways may be quite dramatic and may
fibrosis, and prominent accumulations of pigmented macrophages in adjacent airspace and the bronchiolar lumen. The pigmented macrophages (smokers' macrophages) contain phagocytosed debris from inhaled cigarette smoke and have prominent secondary lysosomes in their cytoplasm. This results in a dirty granular-tan or brown appearance to the cytoplasm. They contain PAS-positive (lysosomes) and finely granular Prussian blue “positive (hemosiderin) material, as well as tiny, irregular flecks of brown-black material.
Table 18.8 Incidental Findings in Lung Tissue
The smoking-related changes in the most distal pulmonary parenchyma usually manifest as centriacinar emphysema with airspace
Asthmatics are predisposed to a number of lung conditions that may lead to lung biopsy, although the asthmatic changes themselves may not be the dominant lesion. These airway changes include goblet cell metaplasia in the airway epithelium, thickening of the basement membrane and submembranous region, smooth muscle hypertrophy and hyperplasia, lymphoid hyperplasia, and a variable infiltrate of eosinophils, lymphocytes, and a few neutrophils, and fibrous tissue in the wall (
). Mucostasis (including Curschmann's
Metaplastic bone, including bone marrow and calcification, is an aging change that is occasionally seen in bronchial cartilages ( 63 ). Metaplastic bone may also be seen in regions of scarring (dystrophic ossification), particularly in apical caps. Small bony nodules may also be seen with no apparent associated pathologic changes. In some older individuals with chronic bronchitis, the bronchial submucosa may have a gray elastotic appearance, particularly in bronchoscopic biopsies.
Carcinoid tumorlets ( 64 , 65 , 66 , 67 ), now referred to simply as tumorlets, and minute pulmonary meningothelial-like nodules ( 67 , 68 , 69 ) are nodular proliferations that are quite common. They may be mistaken for each other, other lesions, or even metastases. Tumorlets ( Figure 18.23 ) represent well-circumscribed proliferations of neuroendocrine cells that usually occur around and within the walls of small airways, particularly in scarred or bronchiectatic airways, and in a small number of patients with airflow destruction. They lack mitotic figures and necrosis; and, while there is a superficial resemblance to small cell carcinoma, they are actually more similar to spindle cell carcinoid tumors. In frozen sections,
tumorlets may be mistaken for other lesions, particularly metastases. This confusion is compounded by the fact that sometimes tumorlets have cellular clusters at the periphery that retract from the surrounding stroma, simulating lymphatic or airspace invasion.
Tumorlets are typically discrete nodules that are bronchiolocentric. The bronchiole is not apparent in A because it has been
Tumorlets are often multiple; some may become large enough to be recognized radiographically and to be removed to exclude carcinoma. Exactly where one draws the line between a carcinoid tumorlet and a carcinoid tumor, particularly in cases with multiple lesions, is quite arbitrary, although a cutoff point of 0.5 cm diameter or larger for carcinoid tumor is reasonable ( 41 ).
Diffuse intrapulmonary neuroendocrine cell hyperplasia (DIPNECH) is closely related to tumorlets, and the two often coexist ( 67 ). Arbitrarily, DIPNECH is defined as a proliferation of neuroendocrine cells limited to the bronchiolar epithelium. According to the World Health Organization (WHO), DIPNECH is defined as a generalized proliferation of scattered single cells, small nodules (neuroendocrine bodies), or linear proliferations of pulmonary neuroendocrine cells (PNCs) that may be confined to the bronchiole and bronchiolar epithelium, include local extraluminal proliferation in the form of tumorlets, or extend to the development of carcinoid tumors ( 67 ). When this proliferation expands and goes beyond the bounds of bronchioles, the designation of tumorlet is appropriate. Tumorlets are most frequently encountered as isolated or occasionally multiple nodules. When DIPNECH is encountered, usually multiple airways
are involved, and the patients may have evidence of airflow obstruction ( 67 ). Similarly, the presence of multiple tumorlets (and multiple carcinoid tumors) should prompt one to search for evidence of DIPNECH and to consider the possibility of clinical evidence of airflow obstruction ( 70 ).
Figure 18.24 Minute pulmonary meningothelial-like nodule. These small parenchymal nodules are sometimes associated with pulmonary veins. A. They are associated with syncytial appearing cells in a collagenous stroma. B. Cytologically, they bear a distinct resemblance to meningothelial cells.
Minute pulmonary meningothelial-like nodules (formerly called minute pulmonary chemodectomas) (
) were originally thought to represent an intrapulmonary proliferation of perivenular chemoreceptor cells (
). However, the
Atypical adenomatous hyperplasia (AAH) is a proliferative epithelial process occurring as small nodular lesions in the lung parenchyma (
). These were first recognized in resection specimens for carcinoma and named bronchioloalveolar cell adenomas (
). Miller found these lesions in 23 (10.74%) of 247 consecutive resection specimens for carcinoma (
). They are most easily recognized grossly in cases that are inflated with Bouin's fixative. The WHO defines AAH as a localized proliferation of mild to moderately atypical cells lining involved alveoli and, sometimes, respiratory bronchioles, resulting in focal lesions in peripheral alveolated lung, usually less than 5 mm in diameter and generally in the absence of underlying interstitial inflammation and fibrosis (
). The lesions are considered a precursor to some nonmucinous bronchioloalveolar carcinomas and mixed-type adenocarcinomas; and the evidence supporting this is epidemiologic, morphologic, morphometric, cytofluorometric, and genetic. Atypical adenomatous hyperplasia generally represents an incidental histologic finding (rare cases have been identified radiologically) and is found in 2 to 4% of routine autopsies of noncancer “
Focal scars (see following), healed granulomatous disease, and organized infarcts are among other incidental nodular lesions occasionally encountered in the lung. Early infarcts have a wedge shape with hemorrhagic necrosis, and the overlying pleura is viable with a fibrinous pleuritis. They often also have a rim of granulation tissue. Older infarcts are often rounded and have a rim of fibrous tissue; they can even be mistaken for healed granulomas. Necrotic tumor nodules sometimes mimic infarcts. Squamous metaplasia is
common in the airspaces adjacent to organizing infarcts and around bronchioles in organizing diffuse alveolar damage; it may be sufficiently exuberant to be mistaken for a neoplastic process. A single anthracosilicotic nodule is an occasional finding that may be accepted as incidental and insignificant if there is no clinical or radiologic evidence of pneumoconiosis. When silicotic nodules are multiple, the occupational history and the possibility of pneumoconiosis should be explored.
Figure 18.25 Atypical adenomatous hyperplasia (AAH). A. In this well-inflated specimen, a 2 to 3 mm diameter lesion is apparent as slight alveolar septal thickening and a proliferation of knob-shaped cells along alveolar walls. B. Cytologically, the cells lining the alveoli have mild to moderate atypia but lack the crowding and marked atypia associated with bronchioloalveolar carcinoma. Some nuclear inclusions characteristic of type II cells are also apparent ( lower left ).
Although extensive parenchymal scarring is usually a pathological process, focal scars a few millimeters in diameter are a common incidental finding in biopsy material. One distinctive form of scar that is frequently observed (and may be identifiable as 2 “3 mm centrilobular nodules in CT
confused with bronchioloalveolar carcinoma. Bronchioloalveolar carcinoma generally has uniform dense cellularity and cellular crowding with abrupt transition to normal alveolar walls, significant cytologic atypia, and lack of ciliated cells. Although AAH tends to have relatively little interstitial widening and fibrosis, AAH enters into the differential diagnosis in this situation.
Figure 18.26 Incidental parenchymal scar. These are typically subpleural and appear to center on alveolar ducts ( A ) and commonly have fascicles of normal appearing smooth muscle ( B ).
Figure 18.27 Ossification. An incidental focus of pulmonary ossification is noted; tissue is from a patient with usual interstitial pneumonia.
In rare instances, mature bone is observed in normal alveoli; it may represent the residue of an organized airspace exudate from chronic passive congestion of mitral stenosis or an ancient organized pneumonia (
). Extensive dystrophic ossification (and rarely calcification) occasionally
Intrapulmonary lymph nodes ( Figure 18.28 ) are not uncommonly encountered in wedge biopsies. They vary from loosely organized microscopic foci of lymphoid tissue to fully developed lymph nodes identified grossly or radiologically.
Micronodular pneumocyte hyperplasia (MNPH) is defined by the WHO (1999) as a multifocal micronodular proliferation of type II cells with mild thickening of the interstitium ( Figure 18.29 ) ( 67 , 75 ). This condition is rare and generally an incidental finding in a biopsy taken for another lesion (usually lymphangioleiomyomatosis). Rarely, MNPH is the sole lesion present, and the lesions may be sufficiently large to be identifiable on CT scans as multiple small nodules. The lesions are typically less than 5 mm in size. They can usually be distinguished from AAH and other causes of alveolar cell hyperplasia by their distinct rounded nodular character at scanning microscopy, the large plump eosinophilic type II cells lacking significant atypia, the slight interstitial collagen deposition within the lesions, and the presence of airspace histiocytes in the regions of the nodules.
Figure 18.28 Intrapulmonary lymph node. There is a relatively large lymph node that appears to be within or adjacent to an interlobular septum in a wedge biopsy from peripheral lung. Reactive follicles are apparent even at scanning power microscopy.
A number of intra-alveolar and intracellular structures are seen in the lung. Small numbers of intra-alveolar macrophages are a normal finding, and an increase in their numbers is nonspecific and a common reaction in smokers ( 43 ). Focal desquamative interstitial pneumonia-like reactions are seen in many pathologic conditions, especially in smokers and in conditions with fibrosis and architectural disorganization ( 46 , 76 ). When hemosiderin is present, causes for alveolar hemorrhage (both primary and secondary) should be excluded.
Corpora amylacea ( 77 , 78 ) are eosinophilic, rounded, slightly lamellated proteinaceous bodies ( Figure 18.30 ) that stain positively with PAS stains and faintly with Congo red stain; they are more common in the lungs of older individuals. Sometimes there is a blue-gray, calcified, or polarizable crystalline particulate body in the center and a macrophage or giant cell response around them. The exact nature and cause of corpora are unclear, but they are of no clinical significance.
Blue bodies ( Figure 18.31 ) are intra-alveolar, lamellated, basophilic, calcified structures found in airspaces associated with alveolar macrophages and giant cells ( 78 ). They are a nonspecific finding in a number of diffuse lung diseases related to accumulation of macrophages and are of no diagnostic significance. They are thought to be related to macrophage catabolism; they are composed primarily of calcium carbonate.
Micronodular pneumocyte hyperplasia (MNPH).
There is a small central nodular region composed of plump type II cells.
The size of the type II cells relative to the surrounding type I cells is apparent in cytokeratin staining.
Cytologically, the type II cells have a
Figure 18.30 Pulmonary corpora amylacea. A. These show a central bluish nidus and a giant cell or macrophage reaction around them. Others may have radiating proteinaceous arrays and show cracking in histologic sections. They are often Congo red “positive. B. Multiple corpora amylacea are seen as an incidental finding associated with organizing pneumonia.
Figure 18.31 Blue bodies. A. and B. Blue bodies are gray or blue, intra-alveolar, calcified, lamellated structures often associated with clusters of macrophages, including giant cells.
Schaumann bodies ( Figure 18.32 ) are similar lamellated, calcified bodies seen in giant cells and associated with granulomas ( 78 , 79 , 80 ). They are also of no diagnostic significance and may be found in granulomas from diverse causes. Schaumann bodies are endogenously derived and may be mistaken for exogenous material since they may be partially birefringent, due to concomitant presence of oxalate crystals (see following).
Asteroid bodies ( Figure 18.33 ) represent a starlike array of crystallized intracellular protein and are seen in giant cells of many granulomatous conditions; other than being aesthetically pleasing, they are nonspecific.
Figure 18.32 Schaumann body. There is a bluish calcified structure associated with surrounding granulomatous inflammation. A lamellated appearance similar to a psammoma body is focally apparent. The pale zones in this case represent loosened oxalate crystals that would be birefringent (see Figure 18.34 ).
Calcium oxalate crystals are
Material similar to Mallory's hyalin ( Figure 18.35 ) may be found in the reactive type II cells of a number of interstitial diseases. It is distinctive, but nonspecific. It may stain for keratin and ubiquitin ( 81 ).
Ferruginous bodies, many of which are asbestos bodies, are indicative of significant inhalational exposure to the ferruginated material, but their presence does not
In virtually any urban adult, one may find short, needlelike, birefringent material (usually silica or silicates) in association with anthracotic pigment ( Figure 18.36 ), either along lymphatic routes in the lung or in regional lymph nodes. Silicates are more brightly birefringent than silica.
The amount of birefringent material may be quite impressive in individuals (particularly smokers) who have no significant occupational exposure. This material should be distinguished from formalin pigment, as well as from surgical glove talc or starch; the latter are limited to handled surfaces and often
Figure 18.33 Asteroid body. An asteroid body in a giant cell is illustrated from a case of asbestosis.
Figure 18.34 Calcium oxalate crystals. Calcium oxalate crystals are commonly associated with Schaumann bodies and granulomatous inflammation and show bright birefringence, as noted in this partially polarized photomicrograph. The association with giant cells is characteristic.
Figure 18.35 Hyalin. Material resembling Mallory's hyalin may be seen in reactive type II cells in a number of acute and chronic conditions.
Figure 18.36 Silica and silicates in normal lung. Birefringent silica and silicate particles are a common nonspecific finding in and around the anthracotic pigment that is so commonly seen in urban adults and smokers.
An occasional nonnecrotizing epithelioid granuloma may be found in the lungs of patients who have no evidence of granulomatous disease; they are analogous to the occasional granuloma seen at many sites in the body. Likewise, cholesterol granulomas or single giant cells containing cholesterol clefts may also be an occasional incidental finding ( Figure 18.37 ). In some instances, the presence of cholesterol granulomas has been linked to prior alveolar hemorrhage, mucostasis, or pulmonary hypertension ( 83 ), but usually no significance can be ascribed to them. Lipogranulomas are an occasional nonspecific finding, said to be more common in diabetics ( 84 ).
An interesting finding is the presence of scattered megakaryocytes in alveolar walls ( Figure 18.38 ), predominantly within alveolar capillaries. Large numbers can be seen, particularly during sepsis. They are of no diagnostic significance but should not be overinterpreted as malignant or virally infected cells. Along with the bone marrow and spleen, the lung acts as a major reservoir for megakaryocytes.
Bone marrow emboli, common in autopsy material, are also seen in biopsy specimens (
). Rarely correlated with any clinically significant process, they may be a consequence of bony trauma or
trauma cannot be implicated, and the marrow emboli are an unexplained incidental finding.
Figure 18.37 Cholesterol granulomas. Granulomas and clusters of giant cells containing cholesterol clefts are a frequent nonspecific finding in interstitial lung disease.
Figure 18.38 Megakaryocytes. A. and B. Megakaryocytes are a common finding in normal lung, often present within alveolar capillaries.
Figure 18.39 Bone marrow embolus. An incidental bone marrow embolus ( right center ) identified in a pulmonary artery in a biopsy from a patient with lymphangioleiomyomatosis ( left ).
Figure 18.40 Thromboemboli in acute lung injury. Small ( A ) or even somewhat large ( B ) fibrin thrombi are commonly present in biopsies showing extensive acute lung injury (A, B). Hyalin membranes are apparent adjacent to the artery in A, and organization is apparent at the top of the field in B.
Recent intravascular thrombi (probably formed in situ) are a relatively common accompanying finding in any severe acute inflammatory lung disease ( Figure 18.40 ), and they should not be considered evidence of pulmonary emboli without corroborating clinical information.
In patients with chronic hemorrhagic, chronic pulmonary congestion, or
Intravascular foreign material is usually birefringent and may have a giant cell reaction. While it usually occurs in intravenous drug abuse (IV talcosis), occasional fragments of
foreign material are seen in patients without a history of drug abuse, perhaps related to intravenous lines during hospitalization or surgery.
Figure 18.41 Iron deposition on elastic tissue ( A, B ). Chronic hemorrhage, in this case due to severe chronic passive congestion, may result in encrustation of interstitial and vascular elastic fibers by hemosiderin. A giant cell reaction is a frequent accompanying finding (A).
The finding of interstitial air, either localized or diffuse, is well known to pediatric lung pathologists and may be an incidental finding in adults who have been on ventilators. Interstitial air can occur as an incidental finding in a region of subpleural fibrosis but also be a significant pathologic finding in its own right (
). The abnormal air-filled spaces resemble honeycombing; however, they lack the expected metaplastic epithelial lining and careful inspection shows either a complete lack of a cellular lining or a histiocytic and giant cell reaction lining the spaces. Interstitial air presenting in this way may be encountered in patients with interstitial lung disease, in patients with a history of pneumothorax, and in and around bullae and blebs. As in ventilated children, interstitial air may be encountered in adults on assisted ventilation and sometimes may be completely missed, being interpreted as tissue
Figure 18.42 Incidental interstitial air. Peculiarly shaped airspaces ( A ) lined by giant cells ( B ) represent interstitial air, which is an occasional incidental finding in patients with interstitial lung disease, including those who have been on positive-pressure ventilation. The case illustrated in A represents an example of nonspecific interstitial pneumonia.
Hilar and peribronchial lymph nodes are rarely
intergranulomatous fibrinoid or hyalinized material), giant cells, and careful clinicopathologic correlation.
Figure 18.43 Histiocyte clusters in hilar nodes. Normal hilar and mediastinal lymph nodes commonly have clusters of histiocytes with variable amounts of dust particles in them. Sometimes they may appear somewhat granulomatous and may be difficult to distinguish from a true granulomatous reaction.
Although multiple intraparenchymal silicotic nodules should make one suspect the possibility of silicosis, anthracosilicotic nodules in hilar nodes are quite common in the absence of silicosis. The nodules are composed of concentric whorled and layered hyalinized collagen and are usually surrounded by a nonpalisaded rim of dust-filled macrophages that contain birefringent material when examined with polarized light. Central degenerative changes may be evident. Silicotic nodules should be distinguished from old/healed granulomatous disease.
Hamazaki-Wesenberg bodies ( 87 ) are small (average: 5 µm in length), yellow-brown intracellular or extracellular structures associated with sinus histiocytes in lymph nodes, especially lung hilar nodes ( Figure 18.44 ). The cause of these bodies is unknown, but they resemble lipofuscin. Positive staining with methenamine silver and PAS stains may lead to their confusion with yeast forms, but their H&E appearance, lack of associated necrosis or inflammation, and positive reaction with Fontana-Masson stain should facilitate their recognition and distinction from fungi.
Changes in the pleura in wedge biopsies may be incidental or part of the underlying pathologic process, and their significance needs to be assessed on an individual case basis.
Incidental Findings in Transbronchial Biopsies
The major artifacts or incidental findings in transbronchial biopsies that lead to misinterpretation include atelectasis (misinterpreted as interstitial pneumonia), bubble artifact (misinterpreted as lipoid pneumonia), and portions of the pleura (either entirely missed or misinterpreted as neoplastic or suspicious for being neoplastic) ( 54 , 55 ). Such portions of pleura may even include some pleural fat, a particularly common finding in fibrosing interstitial pneumonias. The finding of pleural tissue in transbronchial biopsies ( Figure 18.45 ) is not uncommon but also is not well recognized among most pathologists. Strips of reactive mesothelial cells in such specimens may be confused with carcinoma.
Figure 18.44 Hamazaki-Wesenberg bodies. A. Hamazaki-Wesenberg bodies represent yellow-brown oval structures associated with histiocytes, occasionally encountered in hilar and mediastinal lymph nodes. B. Their positive staining with silver stains sometimes leads to confusion with fungi.
As in wedge biopsies, the most common cause of red blood cells in airspaces in transbronchial biopsies is trauma related to the procedure of the biopsy rather than an alveolar hemorrhage syndrome.
Figure 18.45 Visceral pleura in transbronchial biopsies. Transbronchial biopsies directed toward the periphery of the lung may not uncommonly sample portions of the visceral pleura ( A , right ; and B ). These may lead to misdiagnosis, particularly if there is an associated reactive pleuritis.
Effects of Aging
Some of the effects of aging on the lung are shown in
. Calcification and ossification of cartilages in the large airways may be seen. Intimal thickening is an age-related change in pulmonary arteries and veins (
), and apical pulmonary arteries are affected more often (
). Intimal thickening of veins is often hyalin and sclerotic in character, and should be distinguished from the more cellular intimal and muscular proliferation seen in pulmonary veno-
Table 18.9 Effects of Aging seen in Lung Biopsies
The Biopsy that Looks Normal at First Glance
When a lung biopsy for
Although one can argue that interstitial infiltrates that are so subtle as to be overlooked are probably not clinically significant, their recognition is necessary. This situation can arise, for example, with biopsy material from the less severely affected portions of lungs in patients with interstitial pneumonias, in cases in which the inflammatory infiltrate has
been suppressed by steroids or immunosuppressive therapy, and in pathologic entities characterized by patchy inflammation. The presence of inflammatory cells in the perivenular regions and alveolar wall with reactive type II cells is usually indicative of an interstitial pneumonia.
Figure 18.46 Aging change in vessels. In elderly individuals, a hyalin thickening of the intima may be encountered as an incidental finding. Clinical correlation is suggested, since this feature may also be encountered in the setting of pulmonary hypertension.
Table 18.10 Situations in Which a Lung Biopsy May Appear Normal
Figure 18.47 Pulmonary edema. Pulmonary edema may produce a deceptively normal appearance in a biopsy. Attention to septal widening, as noted in the accompanying text, and faint flocculent material in airspaces may be a clue to the diagnosis.
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