Practical Pulmonary Pathology 3rd ed. Kevin O. Leslie, MD

Chapter 5. Developmental and Pediatric Lung Disease

Megan K. Dishop, MD

The diagnostic approach to pediatric lung biopsy differs somewhat from that in the adult patient. Many of the usual questions that arise in adult pulmonary pathology are replaced by separate issues involving abnormal development, altered lung growth due to prematurity, genetic disease, and infections secondary to an immature immune system.¹ the spectrum of diseases observed in the pediatric lung biopsy differs from its adult counterpart, and it is important to approach these biopsies with knowledge of lung development and anatomy. In addition, communication with the clinician, the radiologist, and the surgeon is essential because a tentative list of diagnostic considerations usually can be built on the basis of clinical, radiologic, and intraoperative findings. This chapter covers a spectrum of common and rare entities that the surgical pathologist may encounter when examining biopsied and resected specimens from pediatric patients.

Processing of Pediatric Lung Biopsy Specimens

General processing of lung biopsy specimens is covered in Chapter 2. Recommendations have been published for processing of pediatric biopsy specimens for diffuse lung disease.² A point worthy of emphasis is that in both diffuse and localized disease of the pediatric lung, infection should always be considered, and a substantial portion (one-third to one-half) of the surgical lung biopsy specimen should be sent for cultures if the surgeon has not already sent culture samples directly from the operating room. Touch imprints of the biopsy cut surface can be made and rapidly stained with silver stains for fungi or acid-fast stains for mycobacteria, a technique that is particularly useful for processing of lung biopsy specimens from immunosuppressed or immunocompromised patients. A few small pieces should be retained in glutaraldehyde for electron microscopy, which may have utility in the diagnosis of genetic disorders of surfactant metabolism and viral infections. Additional tissue should be snap-frozen and retained for potential molecular diagnosis of genetic disorders or infectious processes. For patients with suspected autoimmune diseases or chronic hemorrhage syndromes, a piece of lung tissue should be frozen in cryomatrix for possible immunofluorescence study. The remaining lung tissue should be expanded with formalin using a tuberculin syringe or other fine needle by transpleural injection, fixed for approximately 10 minutes, and sectioned for histologic examination. Inflation of pediatric lung biopsy is essential to reproduce the in vivo lung architecture and enables microscopic assessment of alveolar growth and development. In addition to standard hematoxylin and eosin (H&E) stains, many cases of diffuse disease benefit from the addition of connective tissue stains, such as trichrome, Verhoeff-van Gieson, or Movat pentachrome stains, for further evaluation of vascular disease or small-airway scarring, both of which may be under recognized with use of routine stains. Additional staining for microorganisms, iron, glycogen, and alveolar proteinosis should be performed when indicated.

Processing of Pediatric Cystic Lung Lesion Specimens

Gross examination is a critical component of the pathologic assessment of cystic malformations. In particular, the diagnosis of bronchial atresia and intralobar sequestration (ILS) requires attention to gross characteristics that cannot be replicated microscopically. Lesions submitted with a working diagnosis of “congenital cystic adenomatoid malformation” may yield a wide array of pathologic diagnoses, including bronchial atresia, ILS, large cyst congenital pulmonary airway malformation (CPAM), and congenital lobar overinflation (CLO).

Accurate classification of these lesions is facilitated by use of a standard approach to identification of specific anatomic features. The pleura should be examined for accessory pseudofissures, which often mark the contour of underlying maldeveloped lung, typically corresponding to a segmental distribution in bronchial atresia or ILS. ILS is often distinguishable by a segmental region of pulmonary congestion and hemorrhage. The pleural surface is examined for the presence or absence of ligated vessels correlating with entry of an aberrant systemic artery, typically at the medial basal aspect of a lower lobe lesion.

The hilum is examined for a bulging mucocele that may correspond with an atretic bronchial segment. The patent airways at the hilum are inflated with formalin by transbronchial injection, and the distribution of parenchymal expansion is observed, with uninflated segments potentially corresponding to a region of lung distal to a bronchial atresia or ILS. The lobe is sectioned in a parasagittal plane from lateral to medial, preserving the hilum for the last section. Areas of abnormally congested, hyperinflated, or cystic lung parenchyma are documented. A region of microcystic lung parenchyma can be traced with each plane of section toward the hilum until a larger mucus-filled cyst (mucocele) or other dilated airway is recognized, at which point retrograde probing of the airway may assist in documenting the blind-ending point of an atretic bronchus in either isolated bronchial atresia or ILS (bronchial atresia with systemic arterial supply). Microscopic sections should represent central and peripheral aspects of both normal lung and abnormal cystic regions, with interface sections providing a useful histologic contrast between normally developed alveoli and abnormally developed parenchyma. Hyperinflated lobes typical of CLO should prompt attention to the hilar bronchi for identification of stenotic lesions or bronchomalacia. Large unilocular or multilocular cysts need to be sampled extensively to distinguish CPAM from the cystic form of pleuropulmonary blastoma (PPB).

Cysts and Masses

Many pediatric lung biopsies and resections are performed for localized abnormalities within the lungs, and these may be solid or cystic (Box 5.1). A number of clues can be obtained from the history and findings on diagnostic imaging and intraoperative inspection, and these can be helpful in making the correct diagnosis, even before slides have been reviewed. The location of the mass, the presence of cystic or solid areas, the vascular and bronchial supply, and the onset of symptoms can all be useful in narrowing the scope of the differential diagnosis.³

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 are commonly 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 is often unilocular and lined with 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 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. 5.1). 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 with 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 ILS, is appropriate. Radiologic and clinical features may help in further differentiating among these entities.

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. 5.2). 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 round or elongated in shape.^8,9 Abundant mucus and muciphages are typically noted within proximal airway lumens and adjacent air spaces. Bronchial atresia is often 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 CLO, which is characterized by normally developed (albeit markedly distended) air spaces, and ILS, which is distinguished by the additional finding of aberrant systemic arterial supply.³

Figure 5.1 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).

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 there fore “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 (ELSs) represent congenital malformations, the origin of ILSs has been more controversial. More frequent diagnosis in adults has led to the theory that they are postinflammatory lesions with acquired loss of bronchial connection and development of collateral systemic circulation from hypertrophied pulmonary ligament arteries.¹¹ However, ILSs diagnosed prenatally or in association with congenital malformations support the concept that the pathogenic mechanisms for ELS and ILS are similar, and that adult lesions may represent occult malformation detected later in life. Specific features of ELS and ILS, summarized in Table 5.1, are discussed next.¹¹

Figure 5.2 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.

Table 5.1 Pulmonary Sequestration: Extralobar Versus Intralobar

Clinical/Historical Feature	Extralobar Sequestration	Intralobar Sequestration
Location	Outside pleura of lung ("accessory lobe") Commonly, left lung base	Within pleura of lung lobe Lower lobe (98%)
Gross	Pyramidal structure	Congested, hemorrhagic segment(s) of lobe
Age at diagnosis	60% < 6 months	50% > 20 years
Arterial supply	Systemic	Systemic
Origin	Congenital anomaly	Congenital anomaly; possibly acquired in adults
Histologic appearance	CPAM type 2 pattern— hyperinflated air spaces	CPAM type 2 pattern with mucus stasis hyperinflated, hemorrhagic segment(s) of lobe Inflamed, chronic pneumonia

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

ELSs are thought to arise as 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 are usually 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 (Fig. 5.3A). 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 is typically that of type 2 CPAM and less often resembles that of normal lung (Fig. 5.3B and c).^{11,14,15,18-21} Striated muscle is occasionally present within the interstitium of the lesion; this feature is called rhabdomyomatous dysplasia.

Intralobar Sequestration

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 ligament (Fig. 5.4A).²² Radiologic studies can be extremely helpful in supporting the diagnosis.^23,24 Various modalities, including computed tomography (CT) and magnetic resonance imaging, 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 (Fig. 5.4B). The maldeveloped parenchyma shows mucus stasis, identical to that in segmental bronchial atresia (Fig. 5.5A). 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 (Fig. 5.5B).

Figure 5.3 Extralobar sequestration. Extralobar sequestrations are often 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) congenital pulmonary airway malformation pattern (B), and occasionally showing near-normal lung parenchyma with only mildly enlarged air spaces (C).

Figure 5.4 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 is typically present on the inferomedial aspect of the lower lobe. (B) the cut surface is similarly congested and also demonstrates cystic change and mucus stasis, as seen in isolated segmental bronchial atresia.

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 ’Hiese 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 adenoma- toid.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

Figure 5.5 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.

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. 5.6-5.8). 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 represent 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 PPB.^42-48 Large cysts resembling type 1 or type 4 CCAM should be extensively sampled to exclude the presence of small foci of 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 5.6 Congenital pulmonary airway malformation. (A) the type 1 lesion is typically 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.

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 (Fig. 5.6C). 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 is often 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. 5.9A and B). The usual clinical scenario is that of a premature infant with neonatal respiratory distress syndrome (RDS) 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 (Fig. 5.9C). 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.

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. 5.10). Peripheral cysts have been described in the lungs of several patients with Down syndrome.^60-65

Figure 5.7 Congenital pulmonary airway malformation. This type 2 congenital pulmonary airway malformation 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.

Pulmonary Hyperlucency

Several conditions may lead to the radiologic appearance of hyperlucency (Box 5.2). Clinical history and knowledge of the indication for resection are helpful because the pathologic findings can be extremely subtle histologically. The clinical presentation may include shortness of breath, tachypnea, wheezing, or cough, typically in infants. The chest radiograph shows marked lobar enlargement with displacement of the mediastinum. The two most commonly occurring histologic patterns are CLO (so-called congenital lobar emphysema) (in 70% of the cases) and polyalveolar lobe (30%).

Congenital Lobar Overinflation

CLO, or congenital lobar emphysema, occurs when There is overdistention of the normal alveolar parenchyma (Fig. 5.11).^12,66,67 the etiology is variable, but the underlying cause is frequently 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, CLO 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

On gross examination, CLO is characterized by a markedly enlarged lobe, which generally retains its basic shape. Alveoli, alveolar ducts, and respiratory bronchioles are typically 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 (Fig. 5.12).^70-72

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 Although 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 a polyalveolar lobe will be approximately 2 to 3 times that number (Fig. 5.13).

Figure 5.8 Congenital pulmonary airway malformation. (A) Grossly, this congenital pulmonary airway malformation 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.

Figure 5.9 Pulmonary interstitial emphysema (PIE). PIE is caused by air leakage 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.

Figure 5.10 Down syndrome: pulmonary involvement. Peripheral cysts and alveolar simplification are prominent features in some children with Down syndrome.

Disorders of Lung Development

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. 5.14A). Microscopically, the lobular bronchi are surrounded by only a few primitive air spaces, with virtually no alveolar development (Fig. 5.14B). This disorder is uniformly fatal within the first few hours of life and is typically diagnosed at autopsy. Although acinar dysplasia is presumed to be of genetic origin, the etiology is unknown.

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. 5.15). 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 5.11 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 leakage. (B) Microscopically, the overinflated alveoli are enlarged and distended but typically show normal development.

Figure 5.12 Meconium aspiration. Lung injury from meconium aspiration is one of many small-airway processes that can result in regional air-trapping and hyperlucency.

Figure 5.13 Polyalveolar lobe. An increased number of alveoli can be seen within the affected region. Radial alveolar counts can be performed to determine increased values.

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. 5.16), intrauterine chylothorax or pleural effusion, osteochondrodysplasia with small thorax, neuromuscular disorders with poor respiratory effort, and intrathoracic or intraabdominal 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 the section Alveolar Growth Abnormalities).

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. 5.17).

Figure 5.14 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.

Figure 5.15 Congenital alveolar dysplasia. This rare diffuse developmental disorder microscopically resembles the saccular phase of development, despite term gestation.

Figure 5.16 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.

Vascular Disorders

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. 5.18). 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.

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. 5.19). Localized lymphangiectasis is occasionally observed in adults and children and usually 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 5.17 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 Dr. Edwina Popek, Texas Children's Hospital, Houston, Texas.)

Figure 5.18 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.

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. 5.20). Some cases have an associated hemorrhagic “kaposiform” spindle cell component.

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 PAVMs 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 amid lung parenchyma (Fig. 5.21). 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

Complications of Prematurity

Hyaline Membrane Disease

Hyaline membrane disease is a form of acute lung injury seen in neonates and is the pathologic correlate of neonatal 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 the end of 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.¹⁰⁷

Figure 5.19 Lymphangiectasis. Characteristic dilated tortuous lymphatic vessels are present in the subpleural and septal regions.

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. 5.22A). 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 staining (Fig. 5.22B).¹⁰⁸ 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.

Bronchopulmonary Dysplasia

BPD is a chronic lung disease that occurs in a proportion of children who require respiratory support in the neonatal period.^107,110112 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. 5.23A).¹¹⁴¹¹⁶ 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 (Fig. 5.23B). 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 (Fig. 5.23C and D).

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, there by 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

Figure 5.20 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.

Pediatric Interstitial Lung Disease

Attempts to classify pediatric interstitial lung disease (ILD) with the same categories used in adults can result in difficulties in classification and even misclassification.¹ Several of the patterns of disease are similar in adults and in children, but the underlying etiology and prognosis may be different in pediatric cases.¹¹⁸¹²³ So-called usual interstitial pneumonia is virtually nonexistent in children.¹²⁴ Despite these differences, recognition of patterns of interstitial disease remains as important in the diagnosis of diffuse lung disease in children as it is in adults (Box 5.3 and Table 5.2).¹²⁵ the subtypes of ILD are described separately in this section. Even if a precise diagnosis or underlying etiologic disorder cannot be established histologically, the pattern of injury should guide further diagnostic evaluation and in many cases will help to determine prognosis. Assessment of inflammation, and exclusion of infection, may also be helpful in evaluating the potential role of steroid therapy. Practically speaking, the most important diseases to recognize in the neonatal period are the abnormalities of alveolar development and growth, congenital disorders of surfactant metabolism, and alveolar capillary dysplasia. The most important diseases to consider in older children with chronic diffuse lung disease include obliterative bronchiolitis, collagen vascular disease, and hypersensitivity pneumonitis.

Figure 5.21 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.

Data from Swensen SJ, Hartman TE, Mayo JR, Colby TV, Tazelaar HD, Müller NL. Diffuse pulmonary lymphangiomatosis: CT findings. J Comput Assist Tomogr. 1995;19(3):348-352; Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J. 1999;14(4):817-821; Fan LL, Mullen AL, Brugman SM, Inscore SC, Parks DP, White CW. Clinical spectrum of chronic interstitial lung disease in children. J Pediatr 1992;121(6):867- 872; Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120-1128; Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998;157(4 Pt 1):1301-1315.

Figure 5.22 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.

Figure 5.23 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.

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 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. 5.24). However, sometimes a similar pattern is seen on lung biopsy from infants and young children, despite a history of term gestation or lack of RDS 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 (PIG) (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.

Pulmonary Interstitial Glycogenosis (Infantile Cellular Interstitial Pneumonitis)

PIG, also called infantile cellular interstitial pneumonitis, is a disorder that occurs in infants younger 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. 5.25), with a paucity of inflammatory cells.¹²⁶ the spindle cells contain cytoplasmic glycogen granules demonstrable by their periodic acid/ Schiff-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 is generally believed to relate to the severity of any underlying associated pathology, such as chronic neonatal lung disease.

Table 5.2 Histologic Clues in Interstitial Lung Disease

Histologic Finding	Consider
Diffuse type II pneumocyte hyperplasia	Acute lung injury (proliferative diffuse alveolar damage, viral pneumonitis) Genetic disorders of surfactant metabolism
Alveolar macrophages Siderophages	Pulmonary capillaritis Collagen vascular disease Coagulopathy with recurrent hemorrhage Chronic congestive vasculopathy (PVS, VOD, left ventricular obstruction) Idiopathic pulmonary hemosiderosis
Foamy (vacuolated) macrophages	Aspiration pneumonia Metabolic storage disorders Genetic disorders of surfactant metabolism Airway obstruction, postobstructive pneumonia Endogenous lipoid pneumonia in peripheral lung cysts
With eosinophils and fibrin	Eosinophilic pneumonia
Lightly pigmented or nonpigmented	Desquamative interstitial pneumonia Drug reaction
Granular proteinaceous material	Genetic disorders of surfactant metabolism Pulmonary alveolar proteinosis Pneumocystis infection Infection (especially viral pneumonitis with epithelial necrosis)
Organizing pneumonia	Infection Collagen vascular disease Hypersensitivity pneumonitis Idiopathic
Alveolar septal thickening by lymphocytes	—
Bronchiolocentric	Hypersensitivity pneumonitis Infection (e.g., viral bronchiolitis) Aspiration pneumonia Cystic fibrosis Collagen vascular disease Primary ciliary dyskinesia
Nonspecific interstitial pneumonia	Collagen vascular disease Hypersensitivity pneumonitis Genetic disorders of surfactant metabolism (older children)
Lymphocytic interstitial pneumonia	Primary immunodeficiency HIV infection Sjogren syndrome
Follicular bronchiolitis	Primary immunodeficiency (e.g., CVID) HIV infection Epstein-Barr virus infection Collagen vascular disease
Alveolar septal thickening By fibrosis	Bronchopulmonary dysplasia
By increased cellularity	Pulmonary interstitial glycogenosis (infantile cellular interstitial pneumonia)
By edema or muscular arterioles	Vascular/cardiogenic disease
With few central capillaries	Alveolar capillary dysplasia with misalignment of pulmonary veins

CVID, Common variable immunodeficiency; HIV human immunodeficiency virus; PVS, pulmonary vein stenosis; VOD, venoocclusive disease.

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 (CPI), 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 (ATP Binding Casse the Subfamily A Member 3) 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 PAP 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 (Fig. 5.26A-C).^133-137 ’Hiis form of PAP is typically 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 surfactant protein B (SFTPB) gene mutations or dense bodies associated with ABCA3 mutations (Fig. 5.26D) 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.

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 is generally 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. 5.27). Affected patients are frequently immunosuppressed with severe combined immunodeficiency syndrome, leukemia, or lysinuria.^142-145 Pneumocystis infection should also be excluded in this clinical setting.

Chronic Pneumonitis of Infancy

Initially recognized in 1992 and later named by Katzenstein and colleagues in 1995, CPI is a pattern of diffuse ILD 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 (SFTPC) gene (Fig. 5.28).^146-149 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 is generally poor, with development of chronic lung disease or death in a majority of affected infants. SFTPC gene mutations are inherited in an autosomal dominant fashion, and pulmonary fibrosis has been recognized in some families of infants with CPI.

Desquamative Interstitial Pneumonia

In adults, DIP is generally a smoking-related illness resulting in filling of the alveoli with lightly pigmented macrophages. In children, a DIP pattern evokes an array of possible diagnoses including the genetic disorders of surfactant metabolism, particularly surfactant protein B and ABCA3 defects, various viral infections, aspiration, drug reactions, and inhalational injury. In some cases of DIP occurring in early childhood, stabilization has been achieved with systemic corticosteroid treatment.^118,125

Nonspecific Interstitial Pneumonia

The term 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. 5.29), whereas a robust and diffuse lymphocytic interstitial infiltrate of the alveolar walls is the key finding in lymphocytic interstitial pneumonia (Fig. 5.30). 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 Sjogren syndrome,¹²⁵’^152-154 or acquired immunodeficiency due to maternal-fetal transmission of human immunodeficiency virus (HIV).^155-160 Follicular bronchiolitis should also prompt consideration of Epstein-Barr virus infection.

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 are also 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 is usually easily appreciated in acute eosinophilic pneumonia (Fig. 5.31).

Figure 5.26 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 is typically 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.

Figure 5.27 Pulmonary alveolar proteinosis. The differential diagnosis for pulmonary alveolar proteinosis includes the surfactant gene abnormalities, antibody-mediated dysfunction of the granulocyte-macrophage colony-stimulating factor 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.

Figure 5.28 (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 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.

Figure 5.29 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 5.30 Congenital human immunodeficiency virus infection. (A and B) Numerous lymphocyte follicles are present, and the interstitium is broadly expanded by a lymphocytic infiltrate.

Figure 5.31 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 because 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 intraalveolar foamy macrophages and cholesterol clefts is occasionally observed (Fig. 5.32A). Presence of aspirated food particles or interstitial lipid vacuoles, as in exogenous lipoid pneumonia due to mineral oil aspiration (Fig. 5.32B), 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 (Fig. 5.32C).

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 recipients (Fig. 5.33).¹⁶⁸ Asthma and cystic fibrosis also may result in focal obliterative bronchiolitis.

Figure 5.33 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.¹⁶⁹¹⁷¹ 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. 5.34). 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.

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 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. 5.35A 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 venoocclusive disease (Fig. 5.35C), 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 5.34 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.

Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.

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Multiple Choice Questions

1. Which of the following steps is/are appropriate in the processing of lung biopsies from pediatric patients?

A. Touch imprints of the tissue for histochemical evaluation

B. Fixation of a portion of the specimen in glutaraldehyde

C. Submission of tissue from the operating room for cultures

D. Freezing of a portion of the specimen in cryomatrix

E. All of the above

ANSWER: E

2. Which of the following is NOT in the macroscopic differential diagnosis of cystic lung lesions in children?

A. Adenomatoid malformation

B. Intralobar sequestration

C. Congenital lobar overinflation

D. Lymphangioleiomyomatosis

E. Pneumatocele

ANSWER: D

3. Pulmonary sequestration is characterized by:

A. Communication with second-order bronchial lumina

B. Solely systemic vascular supply

C. Exclusive extralobar localization

D. Densely apposed, atelectatic air spaces

E. Multifocal aggregates of eosinophils

ANSWER: B

4. Extralobar pulmonary sequestrations may occasionally contain which ONE of the following heterotopic tissues?

A. Bone

B. Glial nodules

C. Hepatoid anlage

D. Striated muscle

E. Enteric-type epithelium

ANSWER: D

5. Congenital malformations of the pulmonary airways:

A. Are most often seen in stillborns or newborns

B. Represent malformations of each bronchopulmonary segment

C. May be difficult to subclassify in fetal lungs

D. Must be distinguished from pleuropulmonary blastoma

E. All of the above

ANSWER: E

6. Which ONE of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways?

A. Striated muscle

B. Cartilage

C. Mucinous epithelium

D. Embryonic-type mesenchymal tissue

E. Lymphoid aggregates

ANSWER: C

7. Pulmonary interstitial emphysema in children:

A. May be caused by alveolar rupture

B. Can show a bronchovascular distribution

C. Is associated with mechanical ventilation

D. Shows microcysts mantled by giant cells

E. All of the above

ANSWER: E

8. Peripheral cysts in hypoplastic lung tissue have been associated with:

A. Cri-du-chat syndrome

B. Holoprosencephaly

C. Beckwith-Wiedemann syndrome

D. Down syndrome

E. Cornelia de Lange syndrome

ANSWER: D

9. Congenital lobar overinflation:

A. May result from bronchomalacia

B. Is often linked with pleuropulmonary blastoma

C. Is synonymous with congenital malformation of the pulmonary airways, type 0

D. Is idiopathic in 75% of cases

E. Occurs almost exclusively in the lower lobes

ANSWER: A

10. Acinar dysplasia:

A. Features cystic change and enlargement of all lobes

B. Accounts for one of the most common surgical specimens in pediatric lung pathology

C. Demonstrates a lack of alveolarization microscopically

D. Usually becomes manifest clinically at around 2 years of age

E. All of the above

ANSWER: C

11. Pulmonary hyperplasia:

A. Refers to an increased number of alveoli relative to the corresponding conducting airways

B. Shows radial alveolar counts of 20 to 30

C. Is usually associated with proximal airway atresia

D. Is part of the Beckwith-Wiedemann syndrome

E. Is characteristically a consequence of hyaline membrane disease

ANSWER: C

12. Alveolar capillary dysplasia:

A. Is asymptomatic unless pneumonia develops

B. Produces isolated pulmonary venous hypertension

C. Is an alternate diagnostic term for bronchopulmonary dysplasia

D. May be associated with extrapulmonary malformations

E. Is believed to be caused by prolonged mechanical ventilation of infants

ANSWER: D

13. Congenital pulmonary lymphangiectasis:

A. Manifests itself with recurrent chylothorax in children

B. Occurs in all compartments of the lungs except the broncho- vascular bundles

C. Is a “nuisance” condition with no significant mortality

D. Can be imitated morphologically by chronic heart failure

E. None of the above

ANSWER: D

14. Pulmonary arteriovenous malformation:

A. Is always lethal before 5 years of age

B. May produce sudden death in children

C. Is, by definition, a panlobar and multifocal process

D. May be part of the Osler-Weber-Rendu syndrome

E. All of the above

ANSWER: D

15. Which ONE of the following statements concerning hyaline membrane disease of the newborn is FALSE?

A. It is caused by overproduction of structurally abnormal surfactant.

B. It ultimately results from shear stress on alveolar walls.

C. Aggressive mechanical ventilation exacerbates the disorder.

D. It can be complicated by infection with alveolar neutrophilia.

E. It has a morphologic image similar to that of adult respiratory distress syndrome.

ANSWER: A

16. Bronchopulmonary dysplasia:

A. Is caused by partial deletion of chromosome 6q

B. Produces macroscopic pleural pseudofissures

C. Manifests with marked cytologic atypia of bronchial epithelial cells

D. Shows uniform hypoaeration of the most distal airspaces

E. Results in radial alveolar counts in the range of 40 to 50

ANSWER: B

17. Chronic pneumonitis of infancy:

A. Is associated with in utero infection by cytomegalovirus

B. Shows a virtual absence of type II pneumocytes

C. Demonstrates conspicuous remodeling of air spaces

D. Has a good prognosis and can be managed conservatively

E. All of the above

ANSWER: C

18. Obliterative bronchiolitis in children can be associated with all of the following EXCEPT:

A. Adenovirus

B. Influenza

C. Stevens-Johnson syndrome

D. Paragonimiasis

E. Graft-versus-host disease

ANSWER: D

19. Which ONE of the following storage disorders does NOT usually involve the lung parenchyma?

A. Niemann-Pick disease

B. Gaucher disease

C. Glycogen storage disease

D. Mucolipidosis

E. Ceroid lipofuscinosis

ANSWER: E

20. Which of the following is/are potential cause(s) of recurrent intrapulmonary hemorrhage in children?

A. Capillaritis

B. Coagulopathies

C. Milk aspiration syndrome

D. Venoocclusive disease

E. All of the above

ANSWER: E

Case 1

eSlide 5.1

Clinical History

A 4-month-old former term infant boy is referred to the pediatric surgical team for elective resection of a congenital pulmonary airway malformation (CPAM). The lesion was first noted prenatally on a fetal ultrasound at approximately 21 weeks gestation and was described as a multicystic hyperechoic lesion causing moderate enlargement of the right lower lobe. The fetus was monitored and remained stable throughout gestation. He was delivered at 39 weeks gestation and was asymptomatic at birth. Chest computed tomography confirmed a persistent malformation of the right lower lobe, composed of a few small cysts associated with hyperinflation and enlargement of the lobe. He was otherwise healthy, and elective right lower lobectomy was planned. The operative report indicated that There was no evidence of a systemic arterial supply to the right lower lobe. On pathologic examination, serial sections of the lobe in a parasagittal plane (parallel to the hilar plane) revealed spongy, hyperinflated, and crepitant pale, tan parenchyma replacing approximately 50% of the lobe. Mucus was noted in some of the small bronchi and also filled a cystic cavity just deep to the hilum. Retrograde probing of the mucus-filled airways failed to show communication with the large bronchi at the hilum. A representative section of the lesion is provided.

Virtual Slide Microscopic Findings

The section provided shows a region of maldeveloped parenchyma with hyperinflated, enlarged, and simplified airspaces surrounding small airways with slightly increased complexity. Some of the larger airways are distended by mucus stasis. This pattern of maldevelopment is highly associated with intrauterine bronchial obstruction within this segment (or multiple segments) of the lobe. The presence of a subhilar or intraparenchymal cystic space distended by mucus (a central mucocele) is the hallmark of segmental bronchial atresia, and lack of continuity with other proximal airways can be proven on gross examination in many cases. Putting the gross and microscopic findings together, this lobectomy demonstrates a classic example of segmental bronchial atresia with distal hyperinflated maldeveloped parenchyma.

Diagnosis

Bronchial atresia.

The diagnosis of bronchial atresia remains challenging for surgeons, radiologists, and pathologists, although pathologists are perhaps in the best position to correctly recognize this disease through careful gross examination of lobectomy specimens removed for suspected “congenital pulmonary airway malformation.” As indicated earlier, bronchial atresia refers to the obliteration of an airway lumen in utero, classically resulting in distention of the bronchus just distal to the point of atresia, mucus stasis within distal airways, and secondary distension and hyperinflation of distal alveoli. Because of the onset of atresia during active lung development, the morphology of the distal parenchyma becomes altered by the proximal airway obstruction, taking the form of (1) multicystic change and increased respiratory epithelial-lined structures (CPAM type 2 pattern), or (2) alveolar simplification with hyperinflation of the region distal to the point of atresia. Recognition of a segmental or multisegmental distribution of cysts and hyperinflation is an important clue to the diagnosis, both radiographically and at the time of gross examination. Isolated segmental bronchial atresia is relatively common, but underdiagnosed and likely represents the underlying pathology of many cases previously described as CPAM type 2. Once a bronchial atresia pattern is recognized, a systemic arterial supply should be excluded based on clinical findings and gross examination of the lobe. If present, this finding would warrant a diagnosis of intralobar sequestration (that is, bronchial atresia with systemic arterial supply).

References

Kunisaki SM, Fauza DO, Nemes LP, et al. Bronchial atresia: the hidden pathology within a spectrum of prenatally diagnosed lung masses. J Pediatr Surg. 2006;41(1):61-65.

Riedlinger WF, Vargas SO, Jennings RW, et al. Bronchial atresia is common to extralobar sequestration, intralobar sequestration, congenital cystic adenomatoid malformation, and lobar emphysema. Pediatr Dev Pathol. 2006;9:361-373.

Case 2

eSlide 5.2

Clinical History

A 2-week-old boy is delivered at term following an unremarkable pregnancy. He develops respiratory distress shortly after birth associated with hypoxemia. He requires continuous positive airway pressure support initially and then support is escalated, eventually leading to diagnosis of severe persistent pulmonary hypertension. He receives oxygen, inhaled nitric oxide, and sildenafil, and is subsequently placed on extracorporeal membrane oxygenation. Echocardiogram shows a structurally normal heart. A left lung biopsy is performed, and a representative section is provided.

Virtual Slide Microscopic Findings

Sections of the lung biopsy show abnormal lobular architecture with underdeveloped acini and widened interstitium. There is prominent medial hypertrophy of muscular pulmonary arteries and muscularization of intralobular arterioles. The veins and venules are congested and accentuated at low power. The capillary bed is deficient, with decreased numbers of capillary profiles and central position within many of the alveolar walls. That is, the capillaries lack normal juxtaposition with the alveolar epithelial interface. Within the lobules, congested venules are noted in proximity to the thick-walled pulmonary arterial branches (so-called misalignment of pulmonary veins), and There is also variable lymphatic dilation. This constellation of findings is typical of alveolar capillary dysplasia.

Diagnosis

Alveolar capillary dysplasia (ACD)

ACD is a diffuse developmental disorder of the lung affecting the vasculature and the acinar development. The cause of ACD is a genetic abnormality involving the FOXF1 gene on chromosome 16, either a mutation or a deletion, which impairs vascular endothelial growth factor signaling and embryonic vascular development. Larger deletions in this region may be associated with a variety of other congenital malformations, including congenital heart disease (especially hypoplastic left heart syndrome), genitourinary malformations, and gastrointestinal malformations. Indeed, the clinical presentation of pulmonary hypertension may be incorrectly attributed to underlying congenital heart disease, leading to delayed diagnosis in some cases. Lung biopsy remains the gold standard for definitive diagnosis prior to death, although early genetic testing including detection of deletions by chromosomal microarray may allow presumptive diagnosis in the appropriate clinical setting. ACD is a lethal cause of medically intractable neonatal pulmonary hypertension, and the diagnosis typically prompts consideration of lung transplantation or withdrawal of medical support.

References

Boggs S, Harris MC, Hoffman DJ, et al. Misalignment of pulmonary veins with alveolar capillary dysplasia: affected siblings and variable phenotypic expression. J Pediatr. 1994;124:125-128. Pawet S, Partha S, Samarth SB, et al. Genomic and genic deletions of the FOX Gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84(6):780-791.

Ren X, Ustiyan V, Pradhan A, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014;115(8):709-720. Wagenvoort CA. Misalignment of lung vessels: a syndrome causing persistent neonatal pulmonary hypertension. Hum Pathol. 1986;17(7):727-730.

Case 3

eSlide 5.3

Clinical History

A neonate is delivered at 25 3/7 weeks’ gestation to a 38-year-old G2P1 mother following premature onset of labor. The baby shows grunting respirations and retractions, requiring intubation and high-frequency oscillatory ventilation. She is given two doses of intratracheal surfactant therapy and maintained on oxygen and ventilator support. Chest x-ray shows diffuse ground glass opacity. At 10 hours of age, she develops a right tension pneumothorax and bradycardia, requiring emergent chest tube placement and resuscitation. Despite aggressive resuscitation, she has no return of cardiac rhythm and further medical support is withdrawn at 11 hours of age. Representative section of the lungs from autopsy examination is provided.

Virtual Slide Microscopic Findings

The lung tissue is immature with widened interstitium and incomplete alveolarization, consistent with saccular phase of lung development. There are a few scattered hyaline membranes, appearing as ribbon-like bands of fibrin lining the alveolar walls and aggregates of fibrin within the airspaces. There is associated edema fluid. Prominent ovoid and fusiform cysts within the connective tissue of the interlobular septa correspond to acute air-leak phenomenon (pulmonary interstitial emphysema), consistent with history of pneumothorax.

Diagnosis

Hyaline membrane disease with acute pulmonary interstitial emphysema

Discussion

Hyaline membrane disease is the pathologic correlate of respiratory distress syndrome in the neonatal period. It is a form of acute lung

injury caused by immaturity of alveolar epithelial development and insufficient production of surfactant from the type 2 alveolar epithelial cells. Because surfactant is critical for regulating surface tension within alveoli, airspaces with deficient surfactant have a tendency to collapse at end of expiration and are resistant to reexpansion, leading to increased work of breathing, commonly reflected by grunting respiration and retractions in the newborn. The alveolar epithelial cells are also damaged, leading to increased airspace fluid, fibrin, and cell debris, similar to the diffuse alveolar damage that occurs in adult respiratory distress syndrome. Hyaline membranes begin to form at 3 to 4 hours of age and are typically well formed by 12 to 24 hours of age. They are relatively inconspicuous in this case, likely due to mortality prior to 12 hours.

Because of the decreased compliance and increased pressures required to reexpand collapsed alveoli, premature lungs are susceptible to barotrauma, leading to leakage of air into the interstitium and dissection into the interlobular septa and pleura. This phenomenon (acute pulmonary interstitial emphysema) has been reduced with modern neonatal ventilator management but still occurs, and may lead to pneumothorax and cyst formation evidence on chest x-ray.

References

Farrell PM, Avery ME. Hyaline membrane disease. Am Rev Respir Dis. 1975;111(5):657-688. Ikegami M, Jacobs H, Jobe A. Surfactant function in respiratory distress syndrome. J Pediatr. 1983;102(3):443-447.

Case 4

eSlide 5.4

Clinical History

A 2-month-old infant girl was delivered at 28 2/7 weeks’ gestation following a pregnancy complicated by acute chorioamnionitis and premature rupture of membranes. She had respiratory distress at birth, requiring intubation and intratracheal surfactant therapy. She was maintained on high-frequency oscillatory ventilation initially and transitioned to conventional ventilation. Over the next few weeks, she had difficulty weaning from the ventilator, with desaturation during weaning attempts. Chest x-ray showed coarse interstitial markings, and chest computed tomography confirmed the presence of septal thickening and variable areas of hyperinflation. Echocardiogram showed a structurally normal heart, but with thickening of the right ventricle. The severity of her lung disease was thought to be greater than expected for a former 28-week-gestation premature infant, and thoracoscopic lung biopsy was performed at 10 weeks of age to investigate chronic interstitial lung disease.

Virtual Slide Microscopic Findings

The lung biopsy consists of a wedge biopsy of lung parenchyma with abnormal alveolarization. The airspaces are mildly enlarged and simplified, meaning that There is deficient alveolar subdivision compared to that expected at term gestation (38 weeks corrected gestational age). Alveolar duct widening and round distended contours of the alveoli also suggest hyperinflation due to chronic ventilation. Some areas show interstitial widening and increased interstitial cells with ovoid nuclei, bland chromatin, and clear cytoplasm with indistinct cell borders, typical of pulmonary interstitial glycogenosis. The airways are morphologically unremarkable, also without fibrosis. The pulmonary arterial circulation shows mild medial hypertrophy and muscularization of the intralobular arterioles, consistent with clinical evidence of pulmonary arterial hypertension.

Diagnosis

Chronic neonatal lung disease of prematurity (alveolar simplification with pulmonary arteriopathy and pulmonary interstitial glycogenosis)

Discussion

The typical pathologic features of chronic neonatal lung disease due to prematurity differ today compared to the morphology seen in the 1980s and earlier. Historically, premature babies developed hyaline membrane disease, often requiring aggressive ventilation and leading to acute and chronic complications including air leak (pulmonary interstitial emphysema), interstitial fibrosis, and bronchiolar fibrosis. The classic form of chronic lung disease resulting from prematurity took the form of bronchopulmonary dysplasia (BPD), characterized by pleural pseudofissures, alternating segmental atelectasis and hyperinflation, and increased interstitial and interlobular septal fibrosis. With the advent of artificial surfactant therapy and advances in ventilator management in neonatal intensive care units, the severity of acute lung injury and subsequent chronic lung disease has diminished in the modern era, minimizing chronic airway injury, alveolar epithelial injury, interstitial fibrosis, and barotrauma, allowing survival even in extremely premature neonates. Although chronic neonatal lung disease still occurs, the pathologic features are less severe and characterized by impaired alveo- larization, sometimes called “new” BPD. The histologic changes are more subtle than classic BPD and require knowledge of the normal microscopic anatomy of the lung at varying stages of development, including both prenatal and postnatal phases of alveolar development. Alveolar simplification, as demonstrated in this case, is the hallmark and refers to abnormally rounded airspace contours, lacking complete primary and secondary alveolar subdivision expected in the postnatal mature lung. Other changes that commonly accompany alveolar simplification include interstitial widening and mesenchymal cellularity (pulmonary interstitial glycogenosis) and pulmonary arterial medial hypertrophy (arteriopathy). The diminished alveolar wall complexity results in a diminished capillary bed, increased pulmonary vascular resistance, and progressive arteriopathy. When the degree of alveolar simplification is greater than might be expected at the stated gestational age, other factors that might contribute to impaired alveolar development should be sought in the clinical history, including congenital heart disease, pulmonary hypoplasia, chromosomal disorders (Down syndrome, for example), or other forms of acute lung injury in the neonatal period (congenital pneumonia or meconium aspiration, for example). Exclusion of chronic inflammatory or fibrosing lung disease is helpful in further management of these infants and allows reassurance for many families that supportive measures, prevention of infection, and good nutrition will optimize the potential for continued alveolar growth and development over time.

References

Canakis AM, Cutz E, Manson D, O'Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med. 2002;65(11):1557-1565.

Coalson JJ. Pathology of new bronchopulmonary dysplasia. Semin Neonatol. 2003;8(1):73-81. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176:1120-1128.

Case 5

eSlide 5.5

Clinical History

A 4-month-old former term infant boy develops chronic lung disease and is referred for lung biopsy by his pediatric pulmonologist. He was delivered at 39 weeks’ gestation following an uncomplicated pregnancy and developed mild respiratory distress at birth. He was briefly intubated and given surfactant therapy, with no significant response, but was eventually able to be weaned to continuous positive airway pressure and eventually room air, and discharged at 10 days of age. He continued to grow slowly at home over the next several weeks. On a routine follow-up visit to their pediatrician, the baby’s father expressed concern

that he seemed to be breathing faster, and pulse oximetry in the office demonstrated oxygen saturation of 90%, with correction to 97% with supplemental oxygen by nasal cannula. This oxygen requirement led to consultation with a pulmonologist and eventually a high-resolution chest computed tomography, which showed diffuse ground-glass opacity bilaterally, associated with coarse septal markings. Due to concern for interstitial lung disease, a thoracoscopic lung biopsy was performed.

Virtual Slide Microscopic Findings

The wedge lung biopsy demonstrates extensive alveolar remodeling with distortion of airspace contours with variable shapes and sizes of the alveoli, accompanied by diffuse type 2 pneumocyte hyperplasia and diffuse interstitial widening. There are increased macrophages within the alveoli, including aggregates of foamy macrophages, as well as cell debris. Occasional foci of granular and globular dense eosinophilic material indicate pulmonary alveolar proteinosis material, a finding that was confirmed by positivity on periodic acid/Schiff stain. This constellation of findings indicates a form of chronic active interstitial pneumonitis, and in this clinical setting indicates a surfactant dysfunction disorder.

Diagnosis

Genetic disorder of surfactant metabolism due to ATP Binding Casse The Subfamily A Member 3 (ABCA3) deficiency

Discussion

The histologic pattern allows a presumptive diagnosis of a genetic defect in surfactant metabolism and leads to a differential diagnosis including primarily mutations in ABCA3, surfactant protein C (SFTPC), or TTF1/NKX2.1 genes. Neonates with surfactant protein B deficiency are more severely affected and typically die within the first weeks of life. Children with NKX2.1 deficiency may also have hypothyroidism and

choreoathetosis (brain-lung-thyroid syndrome). In this case, a germline pathogenic mutation was identified in the ABCA3 gene, encoding the ATP binding casse The transporter subfamily A3. The pathogenesis of ABCA3 disease is now known to be caused by abnormal transport and retention of ABCA3 protein within type 2 pneumocytes, which are responsible for production of lamellar bodies containing surfactant. In newborns, the morphologic pattern of ABCA3 disease is predominated by abundant alveolar proteinosis material, similar to defects in the surfactant protein B gene (SFTPB), whereas in older children and adolescents, the pattern is more similar to that classically seen with defects in the SFTPC gene, that is, less proteinosis material within airspaces and more extensive interstitial inflammation, fibrosis, and lobular remodeling. Distinction between ABCA3 disease and other genetic disorders of surfactant metabolism may not be possible histologically, but electron microscopy may aid in a more specific diagnosis. In particular, surfactant protein B deficiency is associated with multivesiculated lamellar bodies, whereas ABCA3 deficiency is associated with small, condensed lamellar bodies containing round electron-dense bodies. Definitive diagnosis requires genetic testing on peripheral blood via sequencing of the surfactant genes (SFTPB, SFTPC, ABCA3, TTF1/NKX2.1). The prognosis of ABCA3 disease is highly variable, ranging from early mortality in the newborn period in severe cases, to end-stage lung disease in childhood or adulthood in other cases. ABCA3 disease is expressed in an autosomal recessive fashion, requiring mutation or deletion of both ABCA3 alleles.

References

Bullard JE, Wert SE, Whitsett JA, Dean M, Nogee LM. ABCA3 mutations associated with pediatric interstitial lung disease. Am J Respir Crit Care Med. 2005;172:1026-1031.

Edwards V, Cutz E, Viero S, Moore AM, Nogee L. Ultrastructure of lamellar bodies in congenital surfactant deficiency. Ultrastruct Pathos. 2005;29:503-509.

Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004;350(13):1296-1303.

Whitsett JA, Wert SE, Xu Y. Genetic disorders of surfactant homeostasis. Biol Neonate.2005;87:283-287.