Bronchogenic Cysts

Bronchogenic cysts (or bronchial cysts) are developmental anomalies formed by abnormal budding of the tracheobronchial anlage of the primitive foregut in early development.^4,5 They commonly are found in the anterior mediastinum or along the tracheobronchial tree. Less often, they are found within the pulmonary parenchyma, within or below the diaphragm, or even within the pericardium.^6,7 Patients with bronchogenic cysts can present with infection or obstruction, although frequently these lesions are an incidental radiologic finding.⁵ The cyst often is unilocular and lined by ciliated columnar epithelium. Many bronchogenic cysts communicate with the tracheobronchial tree. On occasion, they show squamous metaplasia or mild chronic inflammation.

Considerations in the differential diagnosis for bronchogenic cyst include esophageal duplication cyst for lesions occurring in the mediastinum and congenital pulmonary airway malformations (CPAMs) for lesions occurring within the substance of the lung. The bronchogenic cyst typically has cartilage plates and submucosal glands in the wall, similar to the normal microscopic anatomy of bronchi (Fig. 4-1). These structures may be sparse but can help differentiate this lesion from the esophageal duplication cyst, which lacks these structures and has a double muscular layer in its wall. Both of these entities can be lined by ciliated mucosa. The bronchogenic cyst lacks connection with alveolar tissue, a feature that aids in its distinction from CPAM. On occasion, with inflamed cysts within the lung, the nature of the specific lesion or underlying disorder may be impossible to ascertain. In such situations, a generic diagnosis of “inflamed intraparenchymal cyst,” accompanied by a differential diagnosis summary that includes abscess, CPAM, bronchogenic cyst, esophageal cyst, and intralobar sequestration, is appropriate. Radiologic and clinical features may help in further differentiating among these entities.

Figure 4-1 Bronchogenic cyst. The wall of a bronchogenic cyst shows features similar to those of a normal bronchus, including submucosal glands (left and center) and cartilage (right).

Bronchial Atresia

Bronchial atresia is one of the most common forms of congenital pulmonary malformation. Atresia of a segmental or subsegmental bronchus classically results in a central mucus-filled cyst (mucocele) at the point of atresia, dilated distal airways with mucous plugs, and hyperinflated microcystic distal parenchyma (Fig. 4-2). Microscopically, the abnormally developed cystic parenchyma has a pattern identical to that described in type 2 CPAM, consisting of increased numbers of abnormal bronchiolar structures surrounded by variably abundant alveolar spaces which are typically distended and either round or elongated in shape.^8,9 Abundant mucus and muciphages typically are noted within proximal airway lumens and adjacent air spaces. Bronchial atresia often is detected prenatally or in infancy as an asymptomatic cystic lesion. Because of interconnection with the normal parenchyma through alveolar pores of Kohn, the abnormal lung distal to a bronchial atresia may potentially become secondarily infected, and presentation in later childhood, adolescence, or adulthood typically is due to symptoms of recurrent pneumonia. The primary considerations in the differential diagnosis are congenital lobar overinflation, which is characterized by normally developed (albeit markedly distended) air spaces, and intralobar sequestration, which is distinguished by the additional finding of aberrant systemic arterial supply.³

Figure 4-2 Bronchial atresia: resected specimens. A, The left upper lobe is enlarged with a region of hyperinflation marked by an irregular pleural pseudofissure. B, The site of bronchial atresia is indicated by a central mucus-filled cyst (mucocele) and surrounding microcystic parenchyma.

Pulmonary Sequestration

Pulmonary sequestration refers to the occurrence of lung tissue that does not communicate with the tracheobronchial tree and that typically has a systemic, rather than pulmonary, arterial supply.^10–13 Such lung tissue is therefore “sequestered” from the usual pulmonary airway and vascular connections. These lesions are further subdivided into an extralobar type, which occurs outside the visceral pleura of the adjacent lung, and an intralobar type, which resides within the visceral pleural investment of a lung lobe. Although there is general agreement that extralobar sequestrations represent congenital malformations, the origin of intralobar sequestrations has been more controversial. More frequent diagnosis in adults has led to the theory that they are post-inflammatory lesions with acquired loss of bronchial connection and development of collateral systemic circulation from hypertrophied pulmonary ligament arteries.¹¹ However, intralobar sequestrations diagnosed prenatally or in association with congenital malformations support the concept that the pathogenic mechanisms for extralobar and intralobar sequestrations are similar, and that adult lesions may represent occult malformation detected later in life. Specific features of extralobar and intralobar sequestrations, summarized in Table 4-1, are discussed next.¹¹

Table 4-1 Pulmonary Sequestration: Extralobar versus Intralobar

CPAM, congenital pulmonary airway malformation.

Modified from Stocker JT. Sequestrations of the lung. Semin Diagn Pathol. 1986;3(2):106–121; and Langston C. New concepts in the pathology of congenital lung malformations. Semin Pediatr Surg. 2003;12(1):17–37.

Extralobar Sequestration

Extralobar sequestrations (ELSs) are thought to arise a a result of abnormal budding from the tracheobronchial anlage. Lying outside the normal lung, these structures appear as “accessory lobes,” completely surrounded by their own visceral pleura.^10–15 ELSs usually are found in the lower thoracic cavity but may be found above, within, or below the diaphragm. On gross inspection, they appear as irregularly ovoid or pyramidal portions of lung tissue surrounded by pleura and with a vascular pole at one edge (see Fig. 4-3A). The radiographic or intraoperative finding of a systemic arterial supply confirms the diagnosis of ELS. The systemic artery can arise from a source above or below the diaphragm.^16,17 The microscopic appearance may vary but the histologic pattern typically is that of type 2 CPAM and less often resembles that of normal lung^{11,14,15,18–21} (see Fig. 4-3B and C). Striated muscle occasionally is present within the interstitium of the lesion; this feature is called rhabdomyomatous dysplasia.

Figure 4-3 Extralobar sequestration. Extralobar sequestrations often are small pyramidal “accessory lobes” with a vascular pole on one side (A). They can have various histologic appearances, most often resembling the type 2 (small cyst) CPAM pattern (B), and occasionally showing near-normal lung parenchyma with only mildly enlarged air spaces (C).

Intralobar Sequestration

Intralobar sequestrations (ILSs) lie within the parenchyma of the lung. Most ILSs occur in the medial area of a lower lobe, and the abnormal systemic elastic artery can usually be identified in the region of the inferior pulmonary ligament²² (Fig. 4-4A). Radiologic studies can be extremely helpful in supporting the diagnosis.^23,24 Various modalities, including computed tomography (CT) and magnetic resonance imaging (MRI), will show a solid or cystic mass that lacks normal bronchovascular patterns. A systemic arterial supply may be confirmed radiologically or at the time of surgery. The gross and microscopic findings are markedly influenced by age at resection and presence or absence of any accrued chronic inflammatory insults (usually secondary infections) within the sequestered lung tissue. In infants with asymptomatic lesions, the lobe contains a segmental region of congestion and hemorrhage due to the high flow of the systemic circulation, accompanied by microcystic parenchyma (see Fig. 4-4B). The maldeveloped parenchyma shows mucus stasis, identical to that in segmental bronchial atresia (Fig. 4-5A). In older children and adults with recurrent pneumonia, the histologic findings are similar in appearance to those in localized bronchiectasis with recurrent infection. Other features include marked acute and chronic inflammation with fibrosis and cyst formation (see Fig. 4-5B).

Figure 4-4 Intralobar sequestration. The sequestered lung is marked on the pleural surface by a region of congestion and hemorrhage. A, An elastic artery of systemic origin typically is present on the inferomedial aspect of the lower lobe. B, The cut surface similarly is congested and also demonstrates cystic change and mucus stasis, as seen in isolated segmental bronchial atresia.

Figure 4-5 Intralobar sequestration. A, Intralobar sequestrations typically show dilated central airways with mucous plugging and peripheral microcystic parenchyma, as well as alveolar hemorrhage due to the high-pressure systemic arterial circulation. B, In older children and adults, there may be evidence of chronic infection, including lymphoid hyperplasia, accumulation of foamy macrophages, and fibrosis.

Congenital Pulmonary Airway Malformations

Congenital malformations of the pulmonary airways (i.e., CPAMs), also called congenital cystic adenomatoid malformations (CCAMs), are masses of maldeveloped lung tissue that are classified according to their gross and microscopic appearance.^12,25–34 These lesions are identified most commonly in stillborn infants or in newborns with respiratory distress, but they can be discovered in adolescents and rarely in adults.³⁵ Stocker and colleagues initially proposed a classification scheme for CCAM that divided these malformations into three subtypes.³⁶ This scheme was later expanded to five subtypes (types 0 to 4), with a subsequent change in terminology from CCAM to CPAM, acknowledging that not all of these malformations are cystic and not all are adenomatoid.³⁷ The overriding principle of this subclassification is that the dominant morphologic constituent of each type of CPAM reflects the morphology of the normal tracheobronchial tree from proximal to distal—that is, from malformed bronchi, to bronchioles, to distal lung (alveolar) tissue. This construct has provided useful morphologic distinctions and will continue to be revised as the pathogenesis of these lesions is better understood. CPAM classification may be difficult in immature or fetal lungs, and an alternate classification has been proposed for fetal lung resections.^33,34

Type 0 CPAM, also called acinar dysplasia, is a rare lesion composed of cartilaginous airways and loose mesenchyme (see later discussion).^38–41 Types 1 to 3 have a common general overall appearance of cystic spaces (distorted airways) with intervening structures more or less resembling alveoli (Figs. 4-6 to 4-8). Type 1 CPAM shows larger cysts, having some bronchial differentiation in that they contain ciliated epithelial lining or mucinous-type epithelium or have cartilage in their walls. Type 2 CPAM shows smaller cystic spaces that resemble ectatic irregular bronchioles, evenly separated from each other by alveolar structures, and represents a histologic pattern that implies intrauterine bronchial obstruction, typically from bronchial atresia or pulmonary sequestration. Type 3 CPAM is a rare solid lesion typically encompassing an entire lobe or lung and resembles pulmonary hyperplasia or immature lung in the early canalicular stage of development. Type 4 CPAM has been described as a peripheral large cyst with thin walls and flattened alveolar-type epithelial lining. Existence of this type is controversial, because it may represent unrecognized, undersampled, or completely differentiated examples of cystic pleuropulmonary blastoma (PPB).^42–48 Large cysts resembling type 1 or type 4 CCAM should be extensively sampled to exclude the presence of small foci of either malignant primitive spindled cells beneath the alveolar epithelium (“cambium layer”) or immature chondroid foci, diagnostic of cystic (type I) PPB. Immunohistochemical staining for myogenin, desmin, and MyoD1 may be helpful in differentiating the cells of PPB from reactive fibroblastic proliferation or cellular mesenchyme in CPAM. Cystic PPBs have potential for recurrence as high-grade tumors, particularly if incompletely resected.

Figure 4-6 Congenital pulmonary airway malformation (CPAM). A, The type 1 lesion typically is composed of a single large trabeculated cyst or a large multilocular cyst, as in this gross specimen. B, Microscopically, the cyst wall is lined by ciliated columnar respiratory-type epithelium with underlying smooth muscle. The lining characteristically interdigitates with the surrounding alveolar parenchyma. C, Small foci of mucigenic epithelium are seen occasionally and are considered the precursor lesions for the rare complication of mucinous bronchioloalveolar carcinoma arising in a congenital cyst.

Figure 4-7 Congenital pulmonary airway malformation (CPAM). This type 2 CPAM shows numerous dilated bronchiolar structures within a background of enlarged irregular alveolar structures. This pattern is associated with intrauterine bronchial obstruction, for example bronchial atresia, intralobar sequestration, and extralobar sequestration.

Figure 4-8 Congenital pulmonary airway malformation (CPAM). A, Grossly, this CPAM shows a spongy mass of abnormal tissue replacing the lobe. B, The abnormally developed parenchyma shows dilated bronchiolar structures surrounded by elongated hyperplastic air spaces.

Although the prognosis in most cases is favorable following resection, there are rare reported cases of patients developing carcinomas in association with CPAM.^49–55 Many of these lesions are mucinous bronchioloalveolar carcinomas, which has led to the proposal that the mucigenic epithelium in type 1 CPAM is preneoplastic (see Fig. 4-6C). Multifocal bilateral mucinous bronchioloalveolar carcinomas after incomplete resection of CPAM have been described in patients as young as 11 years of age.⁵¹ In light of these rare cases, the presence of mucinous epithelium in CPAM and completeness of resection should be documented for follow-up purposes.

Pulmonary Interstitial Emphysema

Pulmonary interstitial emphysema (PIE) results from dissection of air into the interstitial connective tissue of the lung. Rupture of alveoli or disruption of airway walls often is responsible for this phenomenon.^12,56–59 Air accumulates in the interstitium along bronchovascular bundles and interlobular septa, creating cystic spaces that may at first resemble tissue architecturally torn during sectioning (Fig. 4-9A and B). The usual clinical scenario is that of a premature infant with neonatal respiratory distress syndrome receiving mechanical ventilation. Acute PIE usually resorbs over time, but the chronic form persists as cystic lesions lined by fibrous tissue or multinucleate giant cells (see Fig. 4-9C). Grossly, the process can involve both lungs diffusely or may be localized to one or two lobes. Multiple small cysts can be seen to extend along interlobular septa.

Figure 4-9 Pulmonary interstitial emphysema (PIE). PIE is caused by air leak from ruptured alveoli, with dissection of air into the interstitium along bronchovascular bundles and interlobular septa, producing angular elongated cysts, seen grossly (A) and microscopically (B). C, Multinucleate giant cells line the cysts in persistent PIE.

Peripheral Cysts Secondary to Lung Maldevelopment

Hypoplastic lungs, and those damaged in the neonatal period, are susceptible to persistent alterations in alveolar growth. This maldevelopment frequently appears as alveolar enlargement or cysts, particularly in the subpleural areas and peripheral lobules. Microscopic examination reveals irregular air space enlargement with fibrovascular walls lined by alveolar cells (Fig. 4-10). Peripheral cysts have been described in the lungs of several patients with Down syndrome.^60–65

Figure 4-10 Down syndrome: pulmonary involvement. Peripheral cysts and alveolar simplification are prominent features in some children with Down syndrome.

Congenital Lobar Overinflation

Congenital lobar overinflation (CLO), or congenital lobar emphysema, occurs when there is overdistention of the normal alveolar parenchyma^12,66,67 (Fig. 4-11). The etiology is variable, but the underlying cause frequently is a partial or intermittent high-grade obstruction of the bronchus supplying the affected lobe.⁶⁸ Bronchomalacia may result in collapse of the lobar bronchus with expiration, resulting in progressive air-trapping in the affected lobe. The obstruction can occur as a result of other intrinsic factors such as bronchial stenosis, abnormal “kinked” bronchial anatomy, mucosal webs, or mucous plugging. Alternatively, congenital lobar emphysema can be extrinsic as a result of various vascular or neoplastic etiologies. Approximately one half of the cases are idiopathic. The upper lobe is involved in nearly all cases. Lower lobe involvement is highly unusual except in acquired cases in patients with previous hyaline membrane disease or bronchopulmonary dysplasia (BPD). Some cases may arise secondary to trauma from tracheal suctioning during respiratory support.⁶⁹

Figure 4-11 Congenital lobar overinflation. A, The major portion of a lobe in this specimen is massively overinflated, typically as a result of progressive air-trapping by bronchial stenosis or bronchomalacia, resulting in a region of pallor and accentuated air spaces. This specimen also shows focal pulmonary interstitial emphysema due to air leak. B, Microscopically, the overinflated alveoli are enlarged and distended but typically show normal development.

On gross examination, CLO is characterized by a markedly enlarged lobe, which generally retains its basic shape. Alveoli, alveolar ducts, and respiratory bronchioles typically are dilated on histologic examination. Unlike bronchial atresia and CPAM, CLO shows otherwise normal alveolar development, with appropriate numbers of bronchiolar structures and appropriate alveolar septation. The source of obstruction is identified only occasionally by gross and microscopic examination^70–72 (Fig. 4-12).

Figure 4-12 Meconium aspiration. Lung injury from meconium aspiration is one of many small-airway processes that can result in regional air-trapping and hyperlucency.

Polyalveolar Lobe

Polyalveolar lobe occurs when there is an increase in the regional number of alveoli relative to the corresponding conducting airways and arteries.^73–75 Whereas the arteries and airways in these lungs are normal, the alveolar regions are enlarged by an increased number of nearly normal alveoli. The diagnosis can be made by radial alveolar counts, which are performed by counting the number of alveoli transected by a line drawn from the respiratory bronchiole to the nearest acinar edge (pleura or septum).⁷⁶ The normal count varies with age but should be between 5 and 10 for infants, and 10 and 12 for young children. Radial alveolar counts in polyalveolar lobe will be approximately two to three times that number (Fig. 4-13).

Figure 4-13 Polyalveolar lobe. An increased number of alveoli can be seen within the affected region. Radial alveolar counts can be performed to determine increased values.

Acinar Dysplasia

Described in 1986, acinar dysplasia is a rare severe diffuse developmental lung disorder resulting in marked deficiency of acinar development, identical to the entity described as type 0 CPAM.^38–41 The lungs are small, with accentuation of small lobules by white interlobular septa (Fig. 4-14A). Microscopically, the lobular bronchi are surrounded by only few primitive air spaces, with virtually no alveolar development (see Fig. 4-14B). This disorder is uniformly fatal within the first few hours of life and typically is diagnosed at autopsy. Although acinar dysplasia is presumed to be of genetic origin, the etiology is unknown.

Figure 4-14 Acinar dysplasia. In this rare, uniformly fatal form of primary pulmonary hypoplasia, the acinar parenchyma fails to develop. A, The lobules in this specimen are accentuated by thickened interlobular septa. B, On microscopic examination, the parenchyma is seen to be composed of bronchi surrounded by primitive lobules, with lack of subdivision and alveolarization.

Congenital Alveolar Dysplasia

Congenital alveolar dysplasia also is a rare diffuse developmental lung disorder with incomplete air space development.⁷⁷ Relative to those in acinar dysplasia, the air spaces are more numerous and exhibit greater complexity, but completely mature alveoli are lacking. The air spaces show primary septation but insufficient secondary septation, generally resembling the saccular stage of development (Fig. 4-15). This disorder can be difficult to distinguish from prematurity of lungs with superimposed injury and remodeling due to prolonged ventilation, and on a practical level, the diagnosis is reserved for term infants, in whom the disorder is more likely to be a developmental abnormality, rather than an acquired impairment of alveolar growth. The etiology is unknown.

Figure 4-15 Congenital alveolar dysplasia. This rare diffuse developmental disorder microscopically resembles the saccular phase of development, despite term gestation.

Pulmonary Hypoplasia

Pulmonary hypoplasia refers to abnormally small size of the lungs due to limitation of intrauterine development. Although primary forms of hypoplasia exist, this term most commonly refers to the secondary forms of lung hypoplasia in which physical compression of the lungs, by extrathoracic or intrathoracic processes, limits intrauterine growth. Common causes include congenital diaphragmatic hernia (Fig. 4-16), intrauterine chylothorax or pleural effusion, osteochondrodysplasia with small thorax, neuromuscular disorders with poor respiratory effort, and intrathoracic or intra-abdominal lesions with mass effect on thoracic contents.⁷⁸ Grossly, lung hypoplasia can be documented by low lung-to-body weight ratio or by low lung volumes.^79,80 Microscopically, the lobules are small, with a reduced radial alveolar count. Hypoplastic lungs are prone to development of hyaline membrane disease, even at term gestation. Beyond the postnatal period, the simplification of lobules manifests on biopsy as alveolar enlargement and simplification, identical in appearance to chronic neonatal lung disease due to prematurity (see the discussion in section “Alveolar Growth Abnormalities”).

Figure 4-16 Pulmonary hypoplasia. In this case, the hypoplasia was secondary to a large left-sided congenital diaphragmatic hernia. The small left lung is compressed within the superomedial aspect of the thoracic cavity.

Pulmonary Hyperplasia

Pulmonary hyperplasia refers to enlargement of the lungs due to increased mass and volume, typically due to high-grade obstruction of the larynx (laryngeal atresia) or trachea (tracheal compression).^81,82 Morphologically, the air spaces are abnormally elongated and increased in number (Fig. 4-17).

Figure 4-17 Pulmonary hyperplasia. A, In this case, pulmonary hyperplasia was due to laryngeal atresia. The lungs are markedly enlarged and cover the anterior mediastinum. Bilateral rib markings are due to overgrowth and compression within the thoracic cavity. B, Pulmonary hyperplasia is reflected microscopically by abnormally developed tubular and elongated air spaces.

(A, Courtesy of Dr. Edwina Popek, Texas Children’s Hospital, Houston, TX.)

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

Alveolar capillary dysplasia is a disease characterized by a distinctive pattern of diffuse pulmonary vascular maldevelopment (Fig. 4-18). The disease typically manifests clinically soon after birth with profound respiratory distress, often after a brief asymptomatic period.^83–85 The clinical picture is one of severe persistent pulmonary hypertension, and survival beyond the neonatal period is rare.^86–88 Some cases are associated with other visceral malformations, and familial cases have been reported as well, supporting a genetic etiology.⁸⁹ Histopathologic examination reveals abnormal lobular architecture with a diminished number of capillaries within alveolar walls. These alveolar capillaries are abnormally located within the central portion of the septa, rather than adjacent to the alveolar epithelial cells. The pulmonary arteries show marked medial hypertrophy, and the smaller branches show increased muscle, including the arterioles within the alveolar walls. Additional features include misalignment of the pulmonary veins, with congested pulmonary veins abnormally located adjacent to pulmonary arteries within bronchovascular sheaths and congested venules accompanying the hypertrophied arterioles within the lobular parenchyma. Of note, some pulmonary veins may lie in their normal location within interlobular septa, and misalignment of small pulmonary veins and venules within the lobules is more reliably identified. Lymphangiectasia is a variable feature.

Figure 4-18 Alveolar capillary dysplasia. A, Thickened alveolar septa contain capillaries that tend to be centrally located rather than abutting the alveolar lumens. B and C, Congested pulmonary veins are located adjacent to thickened pulmonary arteries in the bronchovascular bundles.

Congenital Pulmonary Lymphangiectasis

Congenital pulmonary lymphangiectasis is a disease of newborns that manifests with dyspnea and cyanosis and often is lethal.^90–95 Panlobar diffuse ectasia of lymphatic channels along normal lymphatic routes (bronchovascular bundles, interlobular septa, and subpleural regions) is characteristic (Fig. 4-19). Localized lymphangiectasis occasionally is observed in adults and children and usually is found as an incidental radiographic abnormality.^96,97 Of note, chronic heart failure or pulmonary venous obstruction can lead to secondary lymphangiectasis, which has a similar histologic appearance, and clinical correlation is important in distinguishing between primary and secondary forms of lymphangiectasia.⁹⁸

Figure 4-19 Lymphangiectasis. Characteristic dilated tortuous lymphatic vessels are present in the subpleural and septal regions.

Diffuse Pulmonary Lymphangiomatosis

Diffuse pulmonary lymphangiomatosis is a rare disease, occurring in children or young adults, in which the normal lymphatic regions show an increased number of complex lymphatic channels.^93,95,99,100 The patients generally present with dyspnea and occasionally with hemoptysis. Microscopic examination reveals increased numbers of anastomosing lymphatic channels with interspersed fibroblasts, collagen, and small vessels distributed along the usual lymphatic routes of the lung. The lymphatics can be more easily observed with use of connective tissue stains and immunohistochemical stains for keratin (to demonstrate these structures in negative relief), or CD31 (which stains the lymphatic endothelium) (Fig. 4-20). Some cases have an associated hemorrhagic “kaposiform” spindle cell component.

Figure 4-20 Diffuse lymphangiomatosis. A, The thin lymphatic channels of lymphangiomatosis can sometimes be difficult to distinguish from alveolar spaces. Use of immunohistochemical markers such as keratin (B), CD31 (C), or the lymphothelial marker D2-40 can be helpful in demonstrating the increased numbers of lymphatic vessels.

Pulmonary Arteriovenous Malformations

Pulmonary arteriovenous malformations (PAVMs) are defined as direct connections between branches of the pulmonary artery and the pulmonary vein.¹⁰¹ Common signs and symptoms are dyspnea, hemoptysis, palpitations, and chest pain. Initial clinical presentation of pulmonary arteriovenous malformations is fairly rare in young children and infants and tends to occur in older children and adults. The diagnosis can be made on clinical and radiologic grounds, followed by pathologic confirmation. Grossly, the malformations can be single or multiple and show ectatic vessels scattered amidst lung parenchyma (Fig. 4-21). Microscopic examination reveals dilated vessels and vascular tangles. The vessels are irregular and are not always in their usual position adjacent to bronchioles, in the case of pulmonary arteries, or in the interlobular septa, in the case of pulmonary veins. Otolaryngologic examination is suggested in patients with PAVM to rule out Osler-Weber-Rendu disease, because approximately one third of patients with single PAVM and one half of patients with multiple PAVMs will have this disease.^101,102 Rare cases of multiple small PAVMs and polysplenia have been described in young children.^103,104

Figure 4-21 Arteriovenous malformation. A, Multiple ectatic vessels may be seen grossly in arteriovenous malformations. B, These enlarged dilated vessels are abnormally distributed within the lung parenchyma.

Hyaline Membrane Disease

Hyaline membrane disease is a form of acute lung injury seen in neonates and is the pathologic correlate of neonatal respiratory distress syndrome (RDS). Hyaline membrane disease arises as a result of surfactant deficiency due to prematurity.¹⁰⁵ Although surfactant granules can be observed in lung cells at a gestational age of 20 weeks, surfactant is not produced in sufficient amounts until 34 weeks. Lack of surfactant can result either from prematurity or, less commonly, from inadequate resorption of lung liquid at birth leading to a dilutional deficiency. Surfactant deficiency results in increased alveolar surface tension, with subsequent resistance to inflation and alveolar collapse at end-expiration. In this process, the alveoli become injured,¹⁰⁶ presumably as a result of shear stresses on the alveolar walls. Increases in either respiratory effort or mechanical ventilation pressures can increase the severity of the injury. This injury in turn leads to diffuse alveolar damage, which is similar in appearance to that observed in adult cases of acute respiratory distress syndrome (ARDS).¹⁰⁷

Grossly, the lungs are firm, red, and consolidated, without significant aeration. Microscopic examination reveals the presence of homogeneous lightly eosinophilic linear material closely adherent to the alveolar surface (Fig. 4-22A). These hyaline membranes may look relatively uniform, but they are actually composed of a myriad of materials, including cytoplasm and nucleoplasm of dead cells, plasma transudate, and amniotic fluid. Hyaline membranes form within 3 to 4 hours of birth and are well developed by 12 to 24 hours. An interesting finding in jaundiced infants with acute lung injury is the presence of yellow hyaline membranes secondary to bilirubin staining¹⁰⁸ (see Fig. 4-22B). Complications of BPD have become relatively rare as a result of improvements in therapy, including surfactant replacement and advances in mechanical ventilation and oxygen therapy.¹⁰⁹ Of note, if numerous neutrophils accompany hyaline membranes, the possibility of acute infection should be considered, because these are not usual components of hyaline membrane disease.

Figure 4-22 Hyaline membrane disease. A, Numerous hyaline membranes are seen lining the alveolar ducts and air spaces. Interstitial fibroblasts and congested alveolar capillaries thicken the alveolar septa. B, Yellow hyaline membranes may be observed in infants with respiratory distress syndrome and hyperbilirubinemia.

Bronchopulmonary Dysplasia

BPD is a chronic lung disease that occurs in a proportion of children who require respiratory support in the neonatal period.^{107,110–112} As the clinical treatment of prematurity has evolved, the pathologic appearance of this disease has changed.¹⁰⁹ The designation was first used for the chronic lung disease that developed subsequently in patients with previous hyaline membrane disease.¹¹³ Examination of the lung in “classic” BPD showed a variegated pattern, with some lobules showing alveolar fibrosis and collapse, whereas adjacent lobules showed overdistention (Fig. 4-23A).^114–116 This appearance of the chronic disease was explained by observations in the pre-existing hyaline membrane disease. Early cases of hyaline membrane disease showed areas of necrotizing bronchiolitis with poor aeration of distal alveolar parenchyma. These areas were subsequently spared from the continuous alveolar insult related to oxygen therapy and mechanical ventilation. As the bronchioles and hyaline membranes healed, airway and interstitial fibroblast proliferation occurred (see Fig. 4-23B). After fibrosis of the injured areas ensued, and healing of the bronchiole was complete, patchy fibrosis was evident in the affected regions, and nearly normal, overdistended alveoli were seen in the spared regions (see Fig. 4-23C and D).

Figure 4-23 Bronchopulmonary dysplasia (BPD). A, Grossly, “classic” BPD shows pleural pseudofissures caused by septal fibrosis, pleural retraction, and regions of lobular hyperinflation. B, In the organizing phase, organization within alveolar ducts of a lobule is evident. The surrounding alveoli are atelectatic. C, In chronic BPD, patchy fibrosis and abnormally enlarged air spaces may be seen. D, Alternating zones of hyperinflation and parenchymal collapse are the result of proximal airway injury and stenosis of variable degree.

In current practice, neonates at risk for hyaline membrane disease are treated with respiratory support and surfactant replacement therapy. This strategy obviates the need for intense oxygen therapy and the mechanical stress that occurred historically. Nevertheless, it is proposed that the lower levels of oxygen treatment in the current regimen result in a generalized uniform alveolar injury.¹⁰⁹ The injured alveoli continue to show maturation by thinning of their septa; however, there is a lack of additional subdivision and branching of the alveolar units of the lobule, thereby leading to an alveolar simplification, so-called “new” BPD.^109,112,117 This lack of normal maturation results in a decrease in the absolute numbers of alveoli. The alveolar walls may be of normal thickness or may be mildly fibrotic. As in polyalveolar lobe, radial alveolar counts can be used in BPD to assess the number of alveoli within lobules.^76,109

Alveolar Growth Abnormalities

Alveolar growth abnormalities are a group of disorders characterized morphologically by the presence of enlarged and simplified air spaces, indicating incomplete or altered alveolarization, either due to prenatal or postnatal factors. A common example of an alveolar growth abnormality, previously discussed, is chronic neonatal lung disease due to prematurity (see earlier section on BPD) (Fig. 4-24). However, sometimes a similar pattern is seen on lung biopsy from infants and young children, despite history of term gestation or lack of respiratory distress syndrome in the neonatal period. Considerations in the differential diagnosis in term infants include pulmonary hypoplasia; disordered lung growth due to underlying chromosomal syndromes (e.g., Down syndrome, other trisomies), malformation syndromes, or congenital heart disease; and disordered lung growth due to poor postnatal alveolarization in the setting of severe neonatal illness. In some patients, impaired alveolarization is considered to be multifactorial—for example, a premature infant with Down syndrome and atrioventricular canal. This morphologic category, described as alveolar growth abnormalities, accounts for the largest subset of diffuse lung disease in infants,¹²³ and attention to alveolar architecture in a well-inflated lung biopsy specimen is essential for diagnosis. Generally speaking, this type of abnormality is likely to be underappreciated by pathologists who interpret predominantly adult lung biopsy specimens, because of the similarity of the enlarged infant air spaces to those in normal adult lung tissue or in emphysematous lung. Lack of interstitial fibrosis or inflammation in most cases also prevents recognition of impaired alveolar architecture as the primary abnormality. Other pathologic findings commonly associated with alveolar growth problems include pulmonary interstitial glycogenosis (discussed next) and secondary pulmonary arteriopathy. In infants with chronic lung disease due to prematurity, these findings may help to explain exacerbation of disease or clinical severity that is disproportionate to that expected for gestational age.

Figure 4-24 Alveolar growth abnormalities. In the post–surfactant era, chronic neonatal lung disease due to prematurity (“new” bronchopulmonary dysplasia) is characterized by impaired alveolarization. Compared with lung from a normal term infant (A), lung from a premature infant shows mildly enlarged and simplified air spaces with deficient septation (B). C, The deficient alveolarization often is accentuated in the subpleural region. A similar histologic pattern is seen in the setting of pulmonary hypoplasia and in some infants with chromosomal syndromes and/or cardiac malformations.

Pulmonary Interstitial Glycogenosis (Infantile Cellular Interstitial Pneumonitis)

Pulmonary interstitial glycogenosis (PIG), also called infantile cellular interstitial pneumonitis, is a disorder that occurs in infants younger than than 6 months of age, with the highest frequency in neonates. These infants develop tachypnea and respiratory distress, and chest radiographs may show bilateral interstitial infiltrates. Microscopic evaluation shows variable thickening of the alveolar septa due to a proliferation of round to oval bland mesenchymal cells (Fig. 4-25), with a paucity of inflammatory cells.¹²⁶ The spindle cells contain cytoplasmic glycogen granules demonstrable by their periodic acid/Schiff (PAS)–positive, diastase-digestible staining characteristics.^127,128 The process may be diffuse or patchy, with great variability in severity. It is vastly underreported in the medical literature and can be identified in the setting of a wide variety of associated conditions, including chronic neonatal lung disease due to prematurity, hypoplasia, congenital heart disease, and even congenital cystic malformations. Although initially proposed to be a genetic or developmental condition,¹²⁹ recognition of the many associated conditions has led to the concept that PIG is a reactive response to injury unique to the infant lung, perhaps reflecting differences in the proliferative capacity of the growing neonatal lung. Affected patients sometimes require ventilatory support, but they tend to show good recovery from their disease over the course of weeks, and steroid therapy has been used with symptomatic improvement in some cases. Prognosis generally is thought to relate to the severity of any underlying associated pathology, such as chronic neonatal lung disease.

Figure 4-25 Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia). Probably a reactive condition unique to the infant lung, pulmonary interstitial glycogenosis often is associated with abnormalities of alveolar growth or pulmonary arteriopathy. A and B, The alveolar septa are thickened by numerous round and spindle mesenchymal cells. C, Periodic acid–Schiff reagent (PAS) staining highlights cytoplasmic glycogen in these cells.

Genetic Disorders of Surfactant Metabolism

The genetic disorders of surfactant metabolism have been associated with several different histologic patterns, including pulmonary alveolar proteinosis (PAP), chronic pneumonitis of infancy (CIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), and idiopathic pulmonary fibrosis.^130,131 The dominant histologic features probably depend on the genotype and the age at presentation. Generally speaking, neonates and infants have more abundant alveolar proteinosis material and more prominent alveolar epithelial hyperplasia, whereas older children and adolescents have less conspicuous globular proteinosis material, less epithelial hyperplasia, more abundant cholesterol clefts, and more abundant fibrosis. Presentation in the neonatal period is typical of surfactant protein B gene mutations and ABCA3 mutations. Presentation in later infancy, childhood, or adolescence is more typical of ABCA3 mutations or surfactant protein C gene mutations.

The histologic patterns associated with these genetic surfactant disorders are discussed next, including practical considerations for differential diagnosis.

Pulmonary Alveolar Proteinosis

PAP is characterized by the accumulation of granular-appearing proteinaceous material within the alveolar spaces¹³² and is subdivided into congenital, acquired, and secondary forms.

Congenital forms of pulmonary alveolar proteinosis are progressive fatal diseases caused by defects in surfactant production and metabolism, and have been reported from mutations of the surfactant protein B gene and the ABCA3 gene, the latter probably related to packaging and secretion of surfactant proteins^133–137 (Fig. 4-26A to C). This form of PAP typically is accompanied by prominent diffuse type 2 alveolar epithelial hyperplasia, increased alveolar macrophages, and occasional cholesterol clefts. Over a period of weeks, diffuse interstitial widening and chronic remodeling of air spaces can be recognized. Electron microscopy may be helpful in assessing lamellar body ultrastructure.^138,139 Presence of multivesicular bodies associated with SFTPB gene mutations or dense bodies associated with ABCA3 mutations (see Fig. 4-26D) help to confirm the diagnostic impression based on histologic pattern, although normal lamellar bodies do not exclude a genetic disorder of surfactant metabolism. Definitive characterization of disease also requires correlation with mutation testing. Considerations in the differential diagnosis for congenital PAP include acquired PAP and secondary PAP.

Figure 4-26 Genetic disorders of surfactant metabolism. Mutations in genes affecting surfactant metabolism result in various histologic patterns in infancy. A and B, Surfactant protein B gene (SFTPB) mutations cause accumulation of alveolar proteinaceous material and increased alveolar macrophages. C, Alveolar proteinosis typically is accompanied by diffuse alveolar epithelial hyperplasia, as in this patient with homozygous ABCA3 gene mutations. D, Electron microscopy confirms the presence of abnormal small lamellar bodies with round dense bodies, characteristic of ABCA3 mutations.

Acquired PAP is unusual in infants and children but may be observed in adolescents. Acquired PAP is thought to arise as a result of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) and is more common in adults. Of interest, an identical pattern of disease has been described in children with genetic mutations in the GM-CSF receptor.^140,141 The same pattern is occasionally seen in children and adolescents with underlying systemic disorders such as leukemia, bone marrow transplantation, and collagen vascular diseases, despite absence of autoantibodies to GM-CSF. PAP in this setting generally is considered to be a problem of macrophage dysfunction and impaired surfactant recycling, although the mechanism of disease is not clear.

Finally, secondary PAP is observed in infants and children with infections causing extensive alveolar epithelial necrosis. The most common infections implicated are those caused by respiratory syncytial virus, cytomegalovirus, and parainfluenza virus. Occasionally, it is possible to recognize increased inflammation or viral cytopathic changes such as multinucleate giant cells in secondary PAP (Fig. 4-27). Affected patients frequently are immunosuppressed with severe combined immunodeficiency syndrome, leukemia, or lysinuria.^142–145 Pneumocystis infection also should be excluded in this clinical setting.

Figure 4-27 Pulmonary alveolar proteinosis. The differential diagnosis for pulmonary alveolar proteinosis includes the surfactant gene abnormalities, antibody-mediated dysfunction of the GM-CSF receptor, Pneumocystis jiroveci infection, and extensive alveolar epithelial necrosis. A and B, The alveolar epithelial necrosis evident in these photomicrographs was due to florid respiratory syncytial virus infection in an immunocompromised child.

Chronic Pneumonitis of Infancy

Initially recognized in 1992 and later named by Katzenstein and colleagues in 1995, CPI is a pattern of diffuse interstitial lung disease in infants and young children, which has now been recognized to be associated with the genetic disorders of surfactant metabolism, most commonly mutations in the surfactant protein C gene (SFTPC)^146–149 (Fig. 4-28). Microscopically, the lungs show alveolar septal thickening by fibroblastic spindle cells, and marked type II pneumocyte hyperplasia. Inflammation and fibrosis are sparse, although conspicuous remodeling of air spaces and interstitial extension of airway smooth muscle are commonly seen. Consolidation by air space macrophages, proteinaceous material, and cholesterol clefts is a frequent finding. Prognosis generally is poor, with development of chronic lung disease or death in a majority of affected infants. Surfactant protein C gene mutations are inherited in an autosomal dominant fashion, and pulmonary fibrosis has been recognized in some families of infants with CPI.

Figure 4-28 A and B, Genetic disorders of surfactant metabolism. Chronic pneumonitis of infancy is a histologic pattern often associated with mutations in the surfactant protein C (SFTPC) gene. This pattern is characterized by remodeled air spaces with thickened septa, sparse interstitial inflammation, prominent type II pneumocyte hyperplasia, clustered foamy alveolar macrophages, and occasional cholesterol clefts.

Nonspecific Interstitial Pneumonia

The term nonspecific interstitial pneumonia (NSIP) is used to describe idiopathic pulmonary diseases that show a uniform expansion of the alveolar septa by inflammation, fibrosis, or both.¹⁵⁰ NSIP is a relatively commonly observed interstitial disease pattern in children,¹¹⁸ but further investigation often allows identification of a specific etiologic disorder. Presence of mild to moderate diffuse lymphocyte infiltrates (NSIP pattern) in the pediatric population raises various diagnostic possibilities including chronic disease due to the genetic disorders of surfactant metabolism (ABCA3, SFTPC), viral pneumonitis, hypersensitivity pneumonitis, and collagen vascular diseases.

Lymphocytic Interstitial Pneumonia and Follicular Bronchiolitis

Follicular bronchiolitis and lymphocytic interstitial pneumonia in children is histologically identical to that observed in adults. The presence of lymphocyte aggregates with germinal centers surrounding bronchioles is characteristic of follicular bronchiolitis (Fig. 4-29), whereas a robust and diffuse lymphocytic interstitial infiltrate of the alveolar walls is the key finding in lymphocytic interstitial pneumonia (Fig. 4-30). Both patterns represent forms of pulmonary lymphoid hyperplasia, and may be observed in the same biopsy. Follicular bronchiolitis can be observed in patients with immune deficiencies such as common variable immune deficiency or hypogammaglobulinemia,^125,151 collagen vascular diseases such as juvenile rheumatoid arthritis or Sjögren syndrome,^{125,152–154} or acquired immunodeficiency due to maternal-fetal transmission of human immunodeficiency virus (HIV).^155–160 Follicular bronchiolitis also should prompt consideration of Epstein-Barr virus infection.

Figure 4-29 Lymphoid hyperplasia. In this example of lung involvement in juvenile rheumatoid arthritis, hemosiderin-filled macrophages are noted in air spaces, prominent lymphocyte follicles (follicular bronchiolitis) are present, and there is overinflation. Cystic changes were noted on computed tomography.

Figure 4-30 Congenital human immunodeficiency virus (HIV) infection. A and B, Numerous lymphocyte follicles are present, and the interstitium is broadly expanded by a lymphocytic infiltrate.

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Hypersensitivity pneumonitis in children is clinically and histologically similar to that seen in adults. The patient generally presents with exercise intolerance and cough. Although the list of antigens in the adult form of the disease is relatively broad as a result of a vast array of occupational exposures, a majority of the cases in children involve either bird antigens (70%) or molds (15%).^161,162 Histologically, hypersensitivity pneumonitis is characterized by a diffuse interstitial lymphocytic infiltrate with bronchiolocentric accentuation and scattered poorly formed granulomas. The air spaces may show consolidation, with macrophages or organizing pneumonia.

Eosinophilic Pneumonia

Eosinophilic pneumonia in children is similar in appearance to that in adults. The causes also are similar, with many cases being secondary to drug reactions, parasite infections, or systemic diseases.¹⁶³ Many cases are idiopathic. The histologic triad of eosinophils, macrophages, and fibrin filling the alveolar spaces usually is easily appreciated in acute eosinophilic pneumonia (Fig. 4-31).

Figure 4-31 Eosinophilic pneumonia. Histopathologic features include interstitial eosinophils and alveolitis, often with organization of hyaline membranes and fibroblast proliferation.

Aspiration Injury

Children with abnormal swallowing function, or gastroesophageal reflux, may aspirate food or gastric fluids into the lung, resulting in aspiration injury. Diagnosis using oil red O stains for lipophages on bronchoalveolar lavage specimens has been suggested. Although this method is relatively sensitive, it is not very specific, since many other diseases including storage diseases, resolving hemorrhage, and resolving pneumonia can result in increased lipophages.¹⁶⁴ The histologic features associated with aspiration are variable and often nonspecific, making aspiration a difficult diagnosis to make with certainty. Accumulation of intra-alveolar foamy macrophages and cholesterol clefts occasionally is observed (Fig. 4-32A). Presence of aspirated food particles or interstitial lipid vacuoles, as in exogenous lipoid pneumonia due to mineral oil aspiration (see Fig. 4-32B), will point to a specific diagnosis. Chronic airway irritation can result in follicular bronchiolitis or organizing pneumonia with granulation tissue plugs occurring within airway lumina. In severe chronic cases, bronchiectasis can occur.¹⁶⁵ Aspirated food particles may elicit a surrounding granulomatous reaction.¹⁶⁶ An interesting but unusual interaction has been described in infants in whom aspiration of fat or oils occurs coincident with the development of infection by rapid-growing mycobacteria, resulting in a lipoid pneumonia with granulomas.¹⁶⁷ Acid-fast bacteria can be demonstrated within the lipid droplets in such cases (see Fig. 4-32C).

Figure 4-32 Aspiration injury. Aspiration injury may be difficult to diagnosis with certainty, but in florid examples as in part A, findings will include abundant foamy macrophages and cholesterol clefts. Food particles and granulomatous inflammation may be seen in older children and adolescents. B, Exogenous lipoid pneumonia due to mineral oil aspiration is characterized by interstitial vacuoles as well as foamy macrophages and areas of reactive alveolar epithelial hyperplasia. C, The interaction of aspirated lipid and rapid-growing mycobacteria creates an unusual lipoid granulomatous pneumonia with vacuoles surrounded by neutrophils and a histiocytic reaction with multinucleate giant cells. Stains for acid-fast bacilli revealed clusters of organisms within the vacuoles in this case.

Obliterative Bronchiolitis

In children, airway obliteration may follow any form of chronic small- and large-airway injury, particularly that resulting in airway mucosal necrosis followed by fibrosis. Common etiologic conditions include preceding severe viral bronchiolitis (e.g., adenovirus or influenza infection), chronic aspiration injury, Stevens-Johnson syndrome, chronic graft-versus-host disease in bone marrow transplant recipients, and chronic airway rejection in lung transplant recipients¹⁶⁸ (Fig. 4-33). Asthma and cystic fibrosis also may result in focal obliterative bronchiolitis.

Figure 4-33 Obliterative bronchiolitis. Obliterated small airways may be a complication of preceding viral bronchiolitis, aspiration injury, graft-versus-host disease, and chronic airway rejection in transplant recipients.

Neuroendocrine Cell Hyperplasia of Infancy (Persistent Tachypnea of Infancy)

Neuroendocrine cell hyperplasia of infancy (NEHI) is a more recently described pathologic correlate to the clinical syndrome of persistent tachypnea of infancy.^169–171 Patients with NEHI are infants and young children with clinical signs and symptoms of chronic tachypnea and hypoxia, often with chronic oxygen requirement, and evidence of hyperinflated lungs on the chest radiograph and patchy perihilar ground-glass opacity on the chest CT scan.¹⁷² Morphologically, the lung biopsy tissue appears almost normal, with only mild lymphoid hyperplasia and subtle alveolar duct expansion (Fig. 4-34). The virtually “normal” biopsy specimen and presence of appropriate alveolarization should prompt further evaluation for NEHI. The diagnosis is made by identifying increased numbers of airway neuroendocrine cells and large neuroepithelial bodies on special stains (e.g., bombesin immunohistochemistry). It remains unknown whether this is a disorder with genetic predisposition or a reactive condition secondary to other forms of small- or large-airway injury. Some children have a history of preceding viral bronchiolitis, and familial cases have been recognized.

Figure 4-34 Neuroendocrine cell hyperplasia of infancy (NEHI). In some infants with persistent tachypnea and chronic oxygen requirement, the degree of clinical severity is disproportionate to pathologic findings on lung biopsy. A, A near-normal lung biopsy specimen with only mild lymphoid hyperplasia and alveolar duct distention raises consideration of NEHI. B, Immunohistochemical staining for bombesin confirms increased numbers of airway neuroendocrine cells. Obliterative bronchiolitis should be ruled out.

Storage Disorders

Lysosomal storage disorders, such as Niemann-Pick disease and mucolipidosis, may manifest with infiltrative lung disease. The histologic hallmark is the presence of confluent foamy, finely vacuolated macrophages, not only within air spaces but also within the interstitium or connective tissue of the bronchovascular bundles, interlobular septa, or pleura. Glycogen storage disease and Gaucher disease may also manifest with accumulation of macrophages within air spaces and within the septal connective tissues.

Vascular Disease as a Cause of Interstitial Lung Disease

Vascular diseases, especially those related to congenital heart defects, can mimic interstitial lung disease (ILD) clinically and radiologically.^{119,120,173–175} Although many of these cases are identified before biopsy, it is important to consider a vascular cause in analysis of a wedge biopsy specimen from a patient being evaluated for ILD.

Hemorrhage Syndromes in Children

Chronic recurrent hemorrhage in children may result from recurrent episodes of pulmonary vasculitis, often small-vessel vasculitides such as capillaritis (Fig. 4-35A and B).^176,177 Other considerations in the differential diagnosis include chronic recurrent hemorrhage due to coagulopathy, chronic hemorrhage due to pulmonary arteriopathy, chronic congestive vasculopathy and pulmonary veno-occlusive disease (see Fig. 4-35C), and idiopathic pulmonary hemosiderosis. Chronic pulmonary hemorrhage has been described in milk aspiration (Heiner syndrome). Of note, idiopathic pulmonary hemosiderosis is a clinicopathologic diagnosis applied when abundant hemosiderin-laden macrophages are present on biopsy, without other associated pathologic changes, and the clinical etiology remains unknown.

Figure 4-35 Pulmonary hemorrhage syndromes. A, Depending on timing of biopsy, chronic hemorrhage syndromes produce abundant hemosiderin-laden macrophages, with or without an admixture of acute alveolar hemorrhage. B, In acute capillaritis, common histopathologic features include subtle infiltrates of neutrophils in the alveolar walls and alveolar spaces, admixed with focal fibrin aggregates and acute hemorrhage. C, Abundant hemosiderin-laden macrophages also should prompt a search for chronic congestive vasculopathy and other causes of venous obstruction, as in this case of pulmonary veno-occlusive disease (Movat pentachrome stain).

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