RESPIRATORY PATHOLOGY

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CHAPTER 12 RESPIRATORY PATHOLOGY

Dealing with the biopsy or resection specimen

Indications for removal of lung tissue

Specimen types

Artefacts, incidental findings and variants of normal

Lung transplantation pathology

Pathology of explanted lungs

Cystic fibrosis

Pathology of the transplanted lung

DEALING WITH THE BIOPSY OR RESECTION SPECIMEN

INDICATIONS FOR REMOVAL OF LUNG TISSUE (Table 12.1)

• Most patients will have had as part of their investigative work-up chest x-ray and CT scan

guides to the area of lung to be sampled

• It must be stressed that a thorough clinical history and knowledge of the imaging are essential in formulating an opinion

Table 12.1 Indications for submission of pediatric lung tissue for histopathological examination

Identification or assessment of primary or secondary neoplasm

Assessment of diffuse interstitial lung disease

Assessment of the pulmonary vasculature

congenital heart disease

pulmonary hypertension of unknown cause

Assessment of respiratory failure or difficulty in ventilation in a neonate

surfactant deficiency

alveolar capillary dysplasia

persistent pulmonary hypertension of the neonate

lymphangiectasia

Removal of congenital malformations or masses obstructing breathing

CPAM

sequestration

bronchial atresia

congenital lobar overinflation

Bronchiectasis Cysts Vascular malformations

Lung transplantation

explanted lungs

surveillance following transplantation

Assessment of possible infection in immunocompromised patients

SPECIMEN TYPES

ARTEFACTS, INCIDENTAL FINDINGS AND VARIANTS OF NORMAL

• When assessing normality, many of the common aging changes described in the adult lung are not applicable to the lungs of children; the following findings may influence interpretation

• Collapse

may suggest increased cellularity, capillary density or interstitial thickening (Fig 12.4)

can be prevented by gentle distension with formalin

• Artificial spaces

too vigorous distension with formalin can created large rounded apparent airspaces

• Hemorrhage

wedge biopsy specimens and transbronchial biopsies may contain fresh hemorrhage

– usually as a result of the procedure

history of hemoptysis indicates search for evidence of hemophagocytosis or hemosiderin-laden macrophages

• Crush

difficult to make any interpretation in crushed areas

may seem to be inflamed

can be problematic with small transbronchial specimens (Fig 12.5)

• Non-specific fibrosis

especially at apices or edges of lobe

fibroelastic thickening of the subpleural region

should not be mistaken for interstitial lung disease (Fig 12.6)

• Embolism of foreign material

small foreign body granulomas common after intravascular intervention (Fig 12.7)

• Vascular changes with aging

a mild degree of venous intimal sclerosis is common in older children

– usually does not cause diagnostic difficulty (Fig 12.8)

bronchial arteries may show considerable longitudinal intimal smooth muscle proliferation (Fig 12.9)

• Megakaryocytes in pulmonary capillaries

normal finding

may be very prominent in cases of sepsis (Fig 12.10)

Fig 12.4 Transbronchial biopsy of lung. The tissue is collapsed and also partly distorted. Assessment of architecture and cellularity is almost impossible on such a specimen.

Fig 12.5 Transbronchial biopsy of lung. There is pinching and crushing of the tissue at the 12 o’clock and 4 o’clock positions. Although some assessment can be made of the non-affected areas, assessment of the affected areas is impossible.

Fig 12.6 Apex of the lung in a 4-year-old boy with idiopathic pulmonary arterial hypertension. The pleura at the lung apices is normally thicker than elsewhere, a difference that increases with aging. It should not be mistaken for pathology. (EVG)

Fig 12.7 Muscular pulmonary artery, the adventitial sheath of which shows foreign-body giant cell reaction to a spicule of refractile foreign material. Such material from the coverings of catheters is almost universally present in the lungs of children who have undergone intravascular intervention. Initially visible as an intimal reaction, the material migrates over time through the vessel wall to occupy the adventitia. It is not of significance, other than as a marker of previous vascular intervention.

Fig 12.8 Mild intimal collagenous thickening of an intralobular vein in a 13-year-old girl. This is regarded as normal. In the very young child there should be no collagen in the intima of the veins. With aging, a thin layer of collagen develops but never to the extent that is seen in older adults. Collagenous thickening of the venous intima may be seen adjacent to sites of inflammation and fibrosis, following transplant or chemotherapy. Prominent and widespread thickening suggests raised pulmonary venous pressure. (EVG)

Fig 12.9 Bronchial artery from an infant aged 6 months. There is intimal longitudinal smooth muscle proliferation causing mild thickening and irregularity of the vessel intima. The longitudinal fibers are cut in cross section and are identified by the surrounding small hoops of elastic tissue protruding into the vessel lumen. (EVG)

Fig 12.10 Transbronchial biopsy showing irregular large dark nuclei of megakaryocytes in capillary lumina. These are a normal finding in any lung biopsy, but their numbers are increased in sepsis.

MALFORMATIONS AND CYSTIC LUNG LESIONS

Introduction

• Nomenclature is confusing for this group

overlap between some entities

similar lesions given different names

different lesions labeled the same

• Many lesions are now detected prenatally by routine scanning and followed up allowing assessment of their development

• Disagreement about details and origins of lesions

increasingly apparent that narrowing or obliteration of the bronchial lumen is a common factor in many of them

• Overarching classification of all cystic lung lesions is suggested (Tables 12.2, 12.3)

Table 12.2 Cystic lung lesions

Bronchopulmonary malformations (see Table 12.3)

Pulmonary hyperplasia and related lesions

laryngeal atresia

solid or adenomatoid CAM (Stocker type 3)

polyalveolar lobe

Congenital lobar over inflation Others

lymphatic/lymphangiomatous cysts

enteric cyst

mesothelial cyst

simple parenchymal cyst

low-grade cystic pleuropulmonary blastoma

(data from Langston 2003)

Table 12.3 Bronchopulmonary malformations

(data from Langston 2003)

CONGENITAL PULMONARY AIRWAY MALFORMATION

• Stocker provided a classification of cystic lung malformations that is almost universally used

• Originally termed Congenital Cystic Adenomatoid Malformation (CCAM)

types I, II and III

– terms still in common use

• Now expanded to types 0–4 (Table 12.4) and renamed Cystic Pulmonary Airway Malformation (CPAM)

• Sometimes problems assigning a particular lesion to one or other of these categories

especially in the fetus

• Type 4 is claimed by others to be a cystic form of pleuropulmonary blastoma (see below)

• A putative derivation from the airways

proximal to distal

– type 0 originating from the trachea/bronchi

– type 4 from the pulmonary acinus

• Cystic adenomatoid malformation no longer used because

not all lesions are cystic

with the exception of type 3 they are not adenomatoid

• Type 4

present with respiratory distress or tension pneumothorax

usually affects one lobe

large air-filled cysts with displacement

large thin-walled cysts

flattened epithelial lining

regarded by many as a type-1 pleuropulmonary blastoma

Fig 12.11 Acinar dysplasia (Type 0 CPAM, Stocker). The lung tissue is composed of bronchial structures without evidence of more distal differentiation. There is abundant edematous interstitium.

Fig 12.12 CPAM type 1. 6-year-old girl. Left lower lobectomy. Photograph of the excised and bisected lobe that contains two large unilocular cysts with slightly trabeculated linings. The larger cyst is 5cm in diameter. Smaller tiny cysts are evident in the surrounding parenchyma.

Fig 12.13 CPAM type 1. Photomicrograph showing the cyst lining is ciliated columnar epithelium with stroma containing inflammatory cells.

Fig 12.14 CPAM type 1. One-month-old baby girl with cystic lesion in left lower lobe of lung. The excised lobe showed obvious cysts, the largest 1.8cm in diameter. The lining of the cysts resembles that in Fig 12.13 but, in addition, there are areas of mucin-secreting epithelium, with a resemblance to gastric epithelium. Some smooth muscle is evident in the cyst walls.

Fig 12.15 CPAM type 2. Macroscopic photograph of a lobe of lung with a well-circumscribed area with a spongy appearance. There are multiple thin-walled cysts.

Fig 12.16 CPAM type 2. Same case as Fig 12.15. A low power view of a section from junction of normal and cystic lung. The multiple small cysts with thin walls are well appreciated as is the relatively well-defined border of the lesion. (H&E)

Fig 12.17 CPAM type 2. Higher power view of the cysts shows their back-to-back arrangement and the uniform bronchiolar type lining. (H&E)

Fig 12.18 CPAM type 2. Striated muscle fibers run through the stroma of the cyst walls; so-called rhadomyomatous dysplasia. Rhabdomyomatous dysplasia may also be seen in other abnormal lungs such as in pulmonary hypoplasia with or without diaphragmatic hernia and may be focal or diffuse throughout the lung parenchyma. The origin of the skeletal muscle is not known. It may represent ingrowth from adjacent structures such as esophagus, but equally it may represent differentiation of pulmonary mesenchyme.

PULMONARY SEQUESTRATION

• Lung tissue that lacks a connection to the bronchial tree

• Usually also has an anomalous systemic arterial supply

• May be within the lung (intralobar) or outside the lung or the thorax (extralobar)

• Rarely a connection to the gastrointestinal tract (usually esophagus) when the lesion is labeled a ‘bronchopulmonary foregut malformation’

EXTRALOBAR SEQUESTRATION

Clinical features

• Usually presents in the first year of life

• Commoner in boys

• Two-thirds occur on the left side

• Frequently associated diaphragmatic defects

• Situated in thorax, retroperitoneum or even pericardium

when in the retroperitoneum can be mistaken for a tumor such as neuroblastoma

Histopathological features

• Pyramidal airless mass (Fig 12.20)

• Systemic arterial supply

very rarely a pulmonary arterial supply

• Drainage to the pulmonary veins, systemic veins or portal veins

• Usually covered by its own pleura

• Composed of lung parenchyma

including bronchi

• Frequently secondary inflammatory changes

• May also show features indistinguishable from CPAM (Fig 12.21)

• Frequent secondary lymphangiectasia

Fig 12.20 Extralobar sequestration. Photograph of the cut surface of a suprarenal mass, clinically thought to be neuroblastoma, from a 4-month-old girl. The specimen is a pyramidal mass 4.5cm in maximum dimension and has a spongy cut surface.

Fig 12.21 Extralobar sequestration. Photomicrograph of the same specimen as Fig 12.20. The lung shows cystic change resembling CPAM type 2. There is some fresh traumatic hemorrhage. There was also chronic inflammation. It contained striated muscle fibers. Cartilage-containing bronchi were also present.

INTRALOBAR SEQUESTRATION

Clinical features

• Many do not present until adult life

• No sex preference

• Equally left- and right-sided

• Mostly affects lower lobes

• Usually no associated abnormality

• Can occur antenatally

Histopathological features

• Situated within the pleural investment of the lung

• Lack a demonstrable bronchial connection but contain air

• Systemic arterial supply (Fig 12.22)

• Venous drainage is to the pulmonary veins

• Can be infected and show secondary changes

fibrosis

cysts

inflammation (Fig 12.23)

• May show changes indistinguishable from CPAM

only the systemic arterial supply allows the case to be termed an intralobar sequestration

• The pulmonary arteries in the sequestered segment may show evidence of pulmonary arterial hypertension (Fig 12.24)

Fig 12.22 Intralobar sequestration. Left lower lobe from a one-year-old boy. The site is typical for intralobar sequestration. A large elastic artery enters the medial aspect of the specimen at the medial diaphragmatic surface. The cut surface showed cystic change.

Fig 12.23 Intralobar sequestration. Photomicrograph of specimen Fig 12.22. There is extensive fresh hemorrhage and there is active inflammation. The bronchi and bronchioles are distended by purulent material. The arteries appear thick-walled.

Fig 12.24 Intralobar sequestration. Photomicrograph of the peripheral vasculature in the same case as Figs 12.22 and 12.23. There is muscularization of the intra-acinar arteries and there is also intimal cellular proliferation, both features indicating pulmonary arterial hypertension, presumably from exposure to the systemic arterial pressure of the anomalous systemic arterial supply. (EVG)

Anomalous arterial supply of normal lung

• Uncommon

• Systemic artery supplies a segment or lobe of lung

• Similar to sequestration

but no bronchus abnormality

• May develop pulmonary arterial hypertensive changes in the vessels of the affected segment

LOBAR EMPHYSEMA

Congenital lobar overinflation

• Overinflation of a lobe of lung

usually middle or upper lobe

• Compression of surrounding normal lung

• May demonstrate partial bronchial obstruction

• Frequently no anatomic cause can be found

• Presents with dyspnea in the first weeks of life

• Lucent area on chest x-ray

• Surgically excised lobe is filled with air

does not collapse after removal (Fig 12.25)

• Microscopically shows distended air spaces (Fig 12.26)

best appreciated by comparing with age-matched control lung

Fig 12.25 Congenital lobar overinflation. Resection of a hyperlucent left upper lobe in a 30-day-old female infant. The roughly triangular overdistended area of lung is evident to the right of the picture. The cut surface shows a few tiny apparent cysts beneath the pleura.

Fig 12.26 Congenital lobar overinflation. Photomicrograph from specimen in Fig 12.25. There is overdistension of alveoli and alveolar ducts (to four to five times the normal diameter). The magnitude of the distension may not be evident until compared with an age-matched control section of lung. Interstitial emphysema was also evident but no other abnormality. No bronchial obstruction could be demonstrated. (H&E)

BRONCHOGENIC CYST

Clinical features

• Usually in the mediastinum near the hilum but may be

Histopathological features

• Contain fluid and mucus (Fig 12.27)

• Respiratory epithelial lining

• Wall with mucous glands and smooth muscle

must contain hyaline cartilage to make the diagnosis (Fig 12.28)

if no cartilage

– better termed a foregut cyst

• Lining may be ulcerated or show squamous metaplasia

• Variable mural inflammation

Fig 12.27 Bronchogenic cyst. Intrapulmonary unilocular cyst with a thin wall and some obstructive changes in the surrounding lung.

Fig 12.28 Bronchogenic cyst. Photomicrograph of a section through the wall of a pulmonary bronchogenic cyst to demonstrate the respiratory epithelial lining and the presence of mucinous glands. No smooth muscle is evident in this field. Crucially for the diagnosis, hyaline cartilage is also present. In the absence of cartilage these cysts are better termed foregut cysts.

HYDATID CYST

INTERSTITIAL EMPHYSEMA

• Dissection of gas from the respiratory tree into the interstitium of the pleura, interlobular septa and bronchovascular bundles

• Frequently associated pneumothorax

• Usually associated with mechanical ventilation in neonates

• Localized form may cause respiratory embarrassment

may mimic CPAM or LE

• Usually does not require lung resection

may be present in lung removed for other reasons

Histopathological features

• Irregular spaces in the interstitium around the bronchovascular bundles, veins and pleura

• May be cystically enlarged

• Lymphatics may be involved

• May be so severe as to leave bronchovascular bundles apparently ‘hanging’ within clear spaces.

• If persistent (PIPE) a surrounding florid foreign-body giant cell reaction occurs (Fig 12.32)

• Easily differentiated from CPAM

may be confused with lymphangiectasia morphologically

– in interstitial emphysema, the spaces lack an endothelial lining

– antibody D2-40 useful in cases of doubt

Fig 12.32 Persistent interstitial pulmonary emphysema. Teenage girl with congenital myopathy and recurrent pneumathoraces. Bullectomy right apex. Photomicrograph showing multiple irregular spaces lined by multinucleated foreign body giant cells. The reaction is typical of that which occurs with persistent air in the tissues.

INTERSTITIAL LUNG DISEASE

Classification

• Recent clinicopathological classification developed for diffuse lung disease in children under 2 years (Table 12.5)

includes many cases of interstitial lung disease

currently no internationally agreed classification for children

Table 12.5 North American classification of diffuse lung disease in children under 2 years

Diffuse developmental disorders

Acinar dysplasia

Congenital alveolar dysplasia

Alveolar capillary dysplasia with misalignment of pulmonary veins

Growth abnormalities

Pulmonary hypoplasia

Chronic neonatal lung disease

Related to chromosomal abnormalities

Related to congenital heart disease

Specific conditions of undefined etiology

Neuroendocrine hyperplasia of infancy

Pulmonary interstitial glycogenosis

Disorders of previously normal (presumed immune intact) host

Infectious and post-infectious processes

Related to environmental agents:

hypersensitivity pneumonitis

toxic inhalation

Aspiration syndromes

Eosinophilic pneumonia

Disorders of the abnormal (immunocompromised) host

Opportunistic infections:

related to therapeutic intervention

Diffuse alveolar damage of unknown etiology

Disorders related to systemic disease

Immune mediated disorders

Collagen vascular disorders

Storage disease

Sarcoidosis

Langerhans cell histiocytosis

Malignant infiltrates

Disorders masquerading as ILD

Arterial hypertensive vasculopathy

Congestive changes related to cardiac dysfunction

Veno-occlusive disease

Lymphatic disorders

Unclassifiable

End-stage lung disease

(data from Deutsch et al 2007)

CONGENITAL SURFACTANT DEFICIENCY

• Deficiency of surfactant protein which leads to two overlapping clinical syndromes

acute respiratory failure in the term neonate

interstitial lung disease in older infants and children

• May be a family history of interstitial lung disease

• All show varying combinations of pathological features

alveolar proteinosis

accumulation of foamy macrophages

type 2 pneumocyte hyperplasia

interstitial thickening

• Note: lipid laden macrophages may also be seen in aspiration, but

in a very young infant with neonatal onset of disease, likely to represent an abnormality of endogenous lung lipid metabolism

Genetics

• Three single-gene disorders to date identified that result in surfactant deficiency

genes encode surfactant protein B (SP-B), surfactant protein C (SP-C) and ABCA3

• SP-B and SP-C are components of surfactant (Hamvas 2006)

• ABCA3 is a membrane component of the type 2 pneumocyte lamellar body that stores surfactant

SP-B gene deficiency

• Severe fatal neonatal onset lung disease

• Autosomal recessive inheritance

• Most show alveolar proteinosis (Fig 12.33)

not all cases

• Type 2 pneumocyte hyperplasia

• Interstitial fibrosis (Fig 12.34)

• Immunohistochemical staining

loss of staining for SP-B

increased staining for SP-A and SP-C

• Electron microscopy (Edwards et al 2005)

no normal lamellar bodies

numerous large multivesicular bodies (Fig 12.35)

Fig 12.33 Congenital surfactant protein B deficiency. Term male infant with severe respiratory distress after delivery. Lung biopsy at 16 days of age. Photomicrograph of lung demonstrating accumulation of granular eosinophilic material in the alveoli. The interstitium is thickened and there is type 2 pneumocyte hyperplasia. Staining for surfactant protein B was negative. Genetic analysis confirmed homozygosity for a missense mutation in the SP-B gene.

Fig 12.34 Congenital surfactant protein B deficiency. Same case as Fig 12.33. The section is stained with anti-cytokeratin antibody MNF 116. This demonstrates clearly the type 2 pneumocyte hyperplasia and the thickening of the interstitium.

Fig 12.35 Congenital surfactant protein deficiency. 8-week-old female infant. Electronmicrograph of type 2 pneumocyte demonstrating abnormal lamellar bodies.

ABCA3 mutations (Bullard et al 2006; Doan et al 2008)

• Clinical features and histopathology similar to those of SP-B deficiency in younger children

• In older children, presents as diffuse interstitial lung disease (Figs 12.36, 12.37)

• Mild respiratory symptoms in the neonatal period

• Electron microscopy shows

small lamellar bodies

densely packed lamellae

electron dense areas

• Likely that many cases of alveolar proteinosis or chronic pneumonitis of infancy in which no mutation has yet been identified may prove to be other forms of surfactant deficiency

Fig 12.36 ABCA3 deficiency. A 3-week-old male child of Middle Eastern origin. Failure to wean from mechanical ventilation. A sibling had died of ‘desquamative interstitial pneumonitis’ several years previously. The ABCA3 gene was subsequently found to be mutated. Biopsy right lung shows a pattern of chronic pneumonitis of infancy. There is thickening of the alveolar septa with florid type 2 pneumocyte hyperplasia. There are collections of macrophages in alveoli but alveolar exudates and inflammatory cell infiltration are not prominent.

Fig 12.37 ABCA3 deficiency. Same specimen as in Fig 12.35, stained with antibody to surfactant protein B. There is strong staining of type 2 pneumocytes.

PULMONARY ALVEOLAR PROTEINOSIS

• Intra-alveolar accumulation of granular eosinophilic material rich in lipid (Fig 12.38)

Fig 12.38 Alveolar proteinosis. 3-year-old girl of Middle Eastern origin with frequent chest infections and acute respiratory distress. Solid lungs on chest x-ray. Surfactant protein genes normal. Biopsy right lung. Died a short time later. Photomicrograph of lung shows distension of the alveoli by eosinophilic proteinaceous material. The alveolar architecture is normal and there is no inflammatory cell infiltrate. Elsewhere in the biopsy there were collections of foamy macrophages.

Clinical features

• Presentation with dyspnea and respiratory distress

high mortality in children

• Most pediatric cases probably due to surfactant deficiency

• Diffuse bilateral infiltrates on x-ray / CT

• Bronchoalveolar lavage is the main investigation

may require biopsy for definitive diagnosis

Fig 12.39 Lysinuric protein intolerance. 4-year-old girl. Failure to thrive, developmental delay, seizures, metabolic acidosis, osteoporosis with fractures and hepatomegaly. Worsening respiratory distress. Diffuse interstitial lung disease on imaging. Photomicrograph of lung biopsy demonstrating mild interstitial thickening with type 2 pneumocyte hyperplasia and alveolar proteinosis.

NIEMANN–PICK DISEASE

• Autosomal recessive metabolic disorder

characterized by accumulation within cells of sphingomyelin

• May also involve the lungs (Guillemot et al 2007)

• Radiologically shows diffuse interstitial infiltrates

• Histologically shows aggregates of foamy macrophages in alveoli and alveolar septa (Fig 12.40)

• Abnormal lamellar accumulation in lysosomes on EM

Fig 12.40 Niemann–Pick disease. 2-year-old girl of Turkish origin with a history of gastro-esophageal reflux disease and Nissen’s fundoplication. increasing respiratory distress. Hepatosplenomegaly. Diffuse interstitial lung disease on imaging. Photomicrograph demonstrating type 2 pneumocyte hyperplasia with accumulation of very vacuolated macrophages in the alveoli. Niemann–Pick disease confirmed on biochemical testing. Similar cells were present in liver and bone marrow.

DESQUAMATIVE INTERSTITIAL PNEUMONITIS (DIP)

• DIP in children is different from that in adults

• Pediatric cases

not associated with cigarette smoking

more aggressive clinical course

may be familial forms

• Likely that many cases, especially in infancy, may represent surfactant protein deficiency

PULMONARY INTERSTITIAL GLYCOGENOSIS

• Presents in first month of life

tachypnea

hypoxemia

• Diffuse, fine interstitial infiltrates and overinflated lungs on CXR

• Negative cultures and negative stains for organisms

• Favorable outcome

• Probably identical to cellular pneumonitis of infancy

NON-SPECIFIC INTERSTITIAL PNEUMONIA (NSIP)

• Does not fit any other specific pattern of interstitial pneumonitis

• Better prognosis than for UIP

Histopathological features

• Uniform lung involvement (Fig 12.46)

• Lymphoid and plasmacytic infiltrate in alveolar septa

• Variable interstitial fibrosis

• Variable but frequent type II pneumocyte hyperplasia

• Variable numbers of alveolar macrophages

• Small foci of intraluminal fibrosis resembling bronchiolitis obliterans organizing pneumonia (BOOP) are common

Fig 12.46 Non-specific interstitial pneumonitis. 5-month-old boy with immunodeficiency and infiltrative lung disease. Difficulty weaning from ventilator. Photomicrograph demonstrating diffuse mild thickening of the interstitium and a focal inflammatory cell infiltrate but no diffuse infiltrate. There is only focal type 2 pneumocyte hyperplasia and accumulation of macrophages in air spaces. The appearance is that of non-specific interstitial pneumonitis.

LUNG TRANSPLANTATION PATHOLOGY

PATHOLOGY OF EXPLANTED LUNGS

• Pulmonary hypertension is described in a separate section

• Lungs explanted for interstitial lung disease show end-stage features

• Diagnostic features of these entities are discussed above

CYSTIC FIBROSIS

• Autosomal recessive

mutation of the CFTR gene

• Pulmonary involvement is universal

affects principally small airways

advanced stage results in severe suppurative lung disease and marked bronchiectasis

mucus plugging of small airways is an early pathological change

– confirmed by CT scanning

• Frequent airway infection with Pseudomonas aeruginosa the most characteristic pathogen

• Repeated cycles of chronic airway infection and inflammation cause bronchiectasis and bronchiolectasis

• Inflammation confined largely to the airway lumen and immediately adjacent lung

even in end stage there are large areas of apparently normal alveolar parenchyma

• Bronchiolitis obliterans is frequent

• Lung abscesses occur frequently

• Subpleural blebs and pneumothorax frequent and serious complications

• Pulmonary arterial hypertension develops

• Hemoptysis is a feature of the late stages of the disease

Macroscopic features

• Explanted lung shows wrinkled pleura with or without fibrous adhesions

may be subpleural bullae

• Thick purulent mucus protrudes from the bronchial resection margin

• Enlargement of the hilar nodes

• Cut surface shows bronchiectasis

dilated tortuous bronchi filled with thick yellow/green pus and mucus (Fig 12.47)

distribution and severity are variable

• Pneumonia is not usually a feature but may be present

• Pulmonary arteries may stand out on the surface

• May be small abscesses scattered throughout the parenchyma

Fig 12.47 Cystic fibrosis. 9-year-old boy with bilateral lung transplant for cystic fibrosis. Photograph demonstrating cut surface of the left lung with severe and extensive purulent bronchiectasis. The bronchial walls are thickened and the lumina dilated causing the bronchi to appear crowded. The lumina contain thick yellow mucopurulent material and there is consolidation and hemorrhage in the intervening lung parenchyma.

Histopathological features

• Destruction of bronchial walls with dense plasma cell infiltrate in the fibrous tissue

• Pus, mucus and necrotic material in the bronchial lumen (Fig 12.48)

Aspergillus hyphae may be present in the lumen (Fig 12.49)

• Variable neutrophil infiltrate in the bronchial wall

• Changes extend into the small bronchi and larger bronchioles

many smaller bronchioles show chronic inflammation

some show narrowing

– others complete fibrous obliteration of their lumina (Fig 12.50)

• Interlobular septa and immediately subjacent alveolar walls may show fibrous thickening and inflammatory cell infiltration

• Parenchyma in between is surprisingly normal

may be small foci of organizing pneumonia

may be necrotizing granulomata caused by infection with atypical mycobacteria (Fig 12.51)

• Vessels in the vicinity of the inflamed airways show intimal thickening

affects both arteries and veins

• May be more generalized changes of pulmonary arterial hypertension

• Bronchial arteries are hypertrophied and frequently obliterated (Fig 12.52)

Fig 12.48 Cystic fibrosis. Explanted lung at low power. Photomicrograph demonstrating dilated lumina and thickened walls of the bronchi with dense material filling them. The lung parenchyma between the inflamed bronchi is minimally affected.

Fig 12.49 Cystic fibrosis. Explanted lung of a 14-year-old girl. Photomicrograph demonstrating dilated bronchial lumen containing mucopurulent material and a colony of Aspergillus. There was no evidence of invasive disease. Aspergillus fumigatus had been grown from sputum pre-transplant. (Grocott stain)

Fig 12.50 Cystic fibrosis. Explanted lung. Obliterative bronchiolitis. Photomicrograph demonstrating outline of a bronchiole with the wall marked by smooth muscle. The lumen is obliterated by vascular fibrous tissue. There is some surrounding scarring in the immediate vicinity of the bronchiole, although the alveoli further afield are normal. This appearance is commonly seen in explanted lungs of patients with cystic fibrosis. The expected accompanying muscular pulmonary artery is not seen, suggesting that it has been involved in the inflammatory process.

Fig 12.51 Cystic fibrosis. Explanted lung. Photomicrograph demonstrating necrotizing granulomatous inflammation with Langhan’s type giant cells. Ziehl–Nielsen staining showed scanty positive bacilli. Myocbacterium avium intracellulare had been cultured from sputum on several occasions pre-transplant. Patients with cystic fibrosis are particularly at risk of infection with non-tuberculous mycobacteria. Infection is uncommon in the first decade but does occur in children under 5 years of age. The prevalence rises with age to around 15% in late adolescence. The main species involved are M. avium complex (approx 72%) and M. abscessus (approx 16%).

Fig 12.52 Cystic fibrosis. Explanted lung with bronchiectasis. Photomicrograph demonstrating section of one bronchial wall showing increase in size of a bronchial artery and muscular proliferation in the intima to the extent of complete luminal occlusion. Bronchial artery hypertrophy and intimal proliferation are common accompaniments of bronchiectasis of whatever cause. (EVG)

PATHOLOGY OF THE TRANSPLANTED LUNG (DISHOP, MALLORY ET AL 2008)

• Survival generally poorer than for adult lung transplant

75% at 1 year

42% at 5 years for children

• Complications

early graft failure (primary graft dysfunction)

pulmonary venous obstruction

Primary graft dysfunction

• Most important early complication

• Most often considered to represent ischemia reperfusion injury

• Presents with non-cardiogenic pulmonary edema with severe hypoxemia

Classification

• Severity classified by the extent and distribution of the mononuclear infiltrates according to a standard classification developed by ISHLT (Table 12.6)

perivenular lymphocytic infiltration in mild forms

more severe forms show infiltrate extension into alveolar septa

lymphocytic bronchiolitis

• May predispose to chronic rejection (obliterative bronchiolitis)

• Grade 0

normal parenchyma

no mononuclear cell infiltrate

no hemorrhage or necrosis (Fig 12.53)

• Grade 3

dense lymphocytic cuffing of venules and arterioles

– extension into perivascular and alveolar septa and airspaces

endothelialitis frequent

eosinophils and sometimes neutrophils present

may be associated with collections of intra-alveolar macrophages and type 2 pneumocyte hyperplasia (Fig 12.55)

• Grade 4

diffuse perivascular, interstitial and airspace infiltrates

alveolar lining cell damage

endothelialitis

hemorrhage, neutrophils and hyaline membranes may be present

very rare to see this grade of rejection

Table 12.6 Revised working formulation for classification and grading of pulmonary allograft rejection

(data from Stewart et al 2007)

Fig 12.53 Transbronchial biopsy post-transplant Grade 0 rejection. Photomicrograph demonstrating a few small lymphocytes present adjacent to the wall of a small vein but they are not circumferential. This is a non-specific finding and does not indicate rejection.

Fig 12.54 Transbronchial biopsy post-transplant Grade A1R rejection. Photomicrograph demonstrating circumferential cuffing of a small vein by lymphoid cells, up to 4–5 cells deep in places. Cells are present in the lumen of the vessel but there is no endothelialitis. There is some fresh hemorrhage in the surrounding alveoli – not usually seen in grade 1 rejection.

Fig 12.55 Transbronchial biopsy post-transplant Grade A3R rejection. Photomicrograph demonstrating a medium-sized vein to the right of the field shows cuffing by lymphoid and lymphoplasmacytoid cells. An eosinophil is seen. There is so-called endothelialitis, with infiltration of lymphoid cells beneath the vessel’s endothelium. The inflammatory cell infiltrate extends into the adjacent alveolar septa. There is type 2 pneumocyte hyperplasia and collections of macrophages in the alveoli.

Airway inflammation

• Intended to apply to bronchioles only

cartilage-containing bronchi should not be assessed

• B0

no bronchiolar inflammation

• B1R

low-grade lymphocytic bronchiolitis

– mononuclear cells in the submucosa

– occasional eosinophils

– no epithelial damage or intra-epithelial lymphocytes

• B2R

high-grade lymphocytic bronchiolitis

– activated lymphocytes in submucosa

– more frequent eosinophils and plasmacytoid cells

– epithelial necrosis or metaplasia and intraepithelial lymphocytic infiltration

– note: large numbers of neutrophils suggests infection rather than rejection (Fig 12.56)

• BX

ungradeable

Fig 12.56 Transbronchial biopsy post-transplant Grade B2R rejection. Photomicrograph demonstrating bronchial epithelium not well preserved, but showing an infiltrate of lymphocytes.

Infectious complications

• More common after lung transplantation than after any other type of solid organ transplant in children

• Accounts for 40% of deaths between one month and one year post transplant

• Causes

greater levels of immunosuppression required

exposure of the graft to the external environment

• Bacterial and fungal infections common in the early post transplant period (Fig 12.57)

pneumonia can clinically mimic severe rejection

• During the first few months post transplant infection with CMV and EBV important

especially in the naive (CMV / EBV negative) recipient

• CMV pneumonitis may be life-threatening (Fig 12.58)

• Highest risk patient is seronegative recipient receiving organs from a donor seropositive for CMV

Fig 12.57 Transbronchial biopsy post-transplant: Aspergillus. Photomicrograph demonstrating admixed with bronchial epithelial cells and debris, hyphae of Aspergillus. The fungus was not identified within tissue.

Fig 12.58 Transbronchial biopsy post-transplant: Cytomegalovirus. Photomicrograph demonstrating a large CMV inclusion in an epithelial cell.

Chronic lung allograft dysfunction

• Due mainly to development of obliterative bronchiolitis

synonymous with chronic rejection

• Immune mediated response to the allograft

• Non-immune mechanisms may also have an important role in development and progression

airway epithelial injury followed by repair

• Risk factors include

frequency and severity of acute rejection episodes

lymphocytic bronchitis

community-acquired viral infections

antibody-mediated rejection

gastro-esophageal reflux

CMV infection

• Diagnosis based on clinical findings and lung function tests

decrease in FEV1

with or without histological confirmation

Histopathological features

• Submucosa expansion and fibrosis of bronchioles

narrowing and ultimately total fibrous occlusion of the bronchial lumen

• Early stages may be accompanied by active lymphocyte inflammation of the small airways

• Changes may be eccentric within the bronchiole

overlain by attenuated or hyperplastic bronchiolar epithelium (Fig 12.59)

• Transbronchial biopsy not a good method of identifying obliterative bronchiolitis

on transbronchial biopsy

– presence of fibrosis adjacent to an artery or with some residual smooth muscle should be suspicious

• Fibrous tissue is lamellar

may be myxoid in its early stages

– becomes densely collagenous

– frequently contains elastic fibers

· connective tissue and elastic stain are useful

• Mucus accumulation or the presence of foamy macrophages in the distal alveoli may be present

Fig 12.59 Obliterative bronchiolitis. 13-year-old boy who underwent bilateral lung transplant for pulmonary arterial hypertension 4 years previously. No episodes of acute rejection. Unexplained drop in lung function. Open lung biopsy. Photomicrograph demonstrating a bronchiole with severe narrowing of its lumen by fibrous tissue. The remnants of smooth muscle of the bronchiolar wall outline its former size. A small polyp of myxoid fibrous tissue protrudes into the lumen at about the 3 o’clock position.

Chronic vascular rejection

• Fibrous intimal thickening of arteries and veins

analogous to coronary artery disease in transplanted hearts

• Not diagnosable on transbronchial biopsy

open lung biopsy necessary for its diagnosis

Antibody mediated (humoral) rejection

• No current consensus on definition, diagnosis or treatment

Post-transplant lymphoproliferative disease (PTLD)

• PTLD greatest frequency post lung transplant compared to other pediatric organ transplants (Fig 12.60)

relatively higher levels of immunosuppression

population of recipients who are frequently EBV negative at transplantation

Fig 12.60 Post-transplant lymphoproliferative disorder. Photomicrograph demonstrating a polymorphous infiltrate of lymphoid cells around bronchi and in the interstitium.

PULMONARY VASCULAR DISEASE

NORMAL PULMONARY VASCULAR ANATOMY

• Normal pulmonary vascular tree (Figs 12.61–12.66) comprises

elastic pulmonary arteries

muscular pulmonary arteries

bronchial and pleural vessels

• Their distinctive histological features are listed in Table 12.7

• Transition from elastic to muscular pulmonary arteries at birth takes place at 200 µm diameter

rather than at the 500 µm in the older child

• During fetal life

media of muscular arteries is thick

lumen narrow

smaller arteries appear almost closed

– vessels open up at birth to permit the rapid fall in pulmonary artery pressure

– over the following two or three weeks there is gradual thinning of the media

Fig 12.61 Normal vascular anatomy in the lobule. Photomicrograph demonstrating, in the center of the lobule, a bronchiole with accompanying muscular pulmonary artery. An interlobular septum is present at the bottom left and contains two pulmonary veins. Note the wide separation of veins and arteries at this level. (EVG)

Fig 12.62 Normal elastic pulmonary artery close to the hilum. Photomicrograph demonstrating well-developed internal and external elastic laminae. There are also multiple small parallel elastic laminae in the media among the smooth muscle cells. The intima shows no thickening and the adventitia is prominent. (EVG)

Fig 12.63 Normal muscular pulmonary artery at the level of a bronchiole. Photomicrograph demonstrating the well developed internal and external elastic laminae with smooth muscle between, endothelium resting on the internal elastic lamina. There is a broad collagenous adventitia. The adventitia shows some dilated lymphatics. The lack of elastic tissue in their walls demonstrates that they are not veins (veins do not accompany the arteries at this level). The artery accompanies a bronchiole. Although smaller in diameter in this section than its bronchiole, artery and airway are usually of more or less similar diameter. (EVG)

Fig 12.64 Normal arteriole. Photomicrograph demonstrating single elastic lamina without any smooth muscle to form a media. The endothelium rests on the elastic lamina. There is a circumferential band of bright red collagen in the adventitia. These arterioles are indistinguishable morphologically from venules. (EVG)

Fig 12.65 Normal vein in an interlobular septum. Photomicrograph demonstrating morphology similar to that of arterioles and venules, although the diameter of the vessel is much larger and in one or two areas there is a suggestion of a few cells in the media. (EVG)

Fig 12.66 Normal bronchial artery. Photomicrograph demonstrating cartilage of the bronchial wall visible to the right of the picture. The artery has the structure of a systemic artery, lacking a well developed external elastic lamina. It has a thick muscular media. (EVG)

Table 12.7 Normal pulmonary vessels

Elastic pulmonary arteries

Extend from pulmonary artery peripherally to a diameter of approximately 1 mm

In the pulmonary trunk and its main branches the elastic fibers are fragmented

Smaller elastic pulmonary arteries show continuous elastic laminae

Smooth muscle cells lie between the elastic laminae

Endothelial layer rests on the internal elastic lamina

Gradual loss of elastic laminae peripherally

Arteries become muscular approximately where the bronchi lose their cartilage

Muscular pulmonary arteries

Muscular media sandwiched between well-developed internal and external elastic laminae

In contrast to systemic arteries (that do not have a well developed external elastic lamina) intima consists only of endothelial cells lying on the internal elastic lamina following branching of the bronchi

Supernumerary arteries that arise obliquely into the parenchyma

Roughly of the same diameter as the bronchus that it accompanies

Media normally occupies 3–7% of the external diameter

Peripherally, muscular arteries gradually lose their muscular coat

Below a diameter of approx 100 µm become arterioles

Pulmonary arterioles

Non-muscular vessels

Morphologically indistinguishable from venules

Pulmonary veins

Contain collagen fibers

Interrupted elastic laminae

Some smooth muscle cells

Run in interlobular septa

Bronchial arteries

Accompany bronchi

Structure of systemic arteries relatively thick muscular media

Incompletely developed external elastic lamina

Pulmonary lymphatics

Not present in alveolar septa

Numerous in interlobular septa and around bronchi

PULMONARY HYPERTENSION

• Sustained rise in pulmonary arterial blood pressure from any cause will give rise to a series of characteristic histological changes (Gorenflo et al 2003, Simmonneau et al 2004)

• Symptoms in children with pulmonary hypertension vary depending on the cause but include

dyspnea

dizziness

syncope

• Sudden death may be the first presentation

rare

Classification

• As agreed at the Third World Pulmonary Hypertension Symposium 2003

five main categories (Table 12.8) based on common clinical features

• Specifically, among the developmental disorders are conditions seen with some frequency in pediatric cases including:

hyaline membrane disease

bronchopulmonary dysplasia

congenital diaphragmatic hernia

pulmonary hypoplasia

alveolar capillary dysplasia

cystic fibrosis

Table 12.8 Clinical classification of pulmonary hypertension

Pulmonary hypertension associated with disorders of the respiratory system and/or hypoxia

Chronic obstructive pulmonary disease

Interstitial lung disease

Sleep-disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Developmental abnormalities

Pulmonary hypertension resulting from chronic thrombotic and/or embolic disease

Thromboembolic obstruction of proximal pulmonary arteries

Thromboembolic obstruction of distal pulmonary arteries

Pulmonary embolism (tumor, parasites, foreign material)

Compression of the pulmonary vessels (fibrosing mediastinitis, adenopathy, tumors)

Histopathological features

• Elastic pulmonary arteries

may show atheromatous intimal plaques (Fig 12.67)

• Muscularization of the arterioles (Fig 12.74)

• In cases with a significant venous component the veins show

wall thickening with realignment of the elastic tissue such that they resemble arteries

– so-called arterialization (Fig 12.75)

concentric intimal fibrous thickening (Fig 12.76)

in veno-occlusive disease show fibrous and myxoid occlusion of the vessels (Fig 12.77)

Fig 12.67 Pulmonary arterial hypertension: atheroma elastic pulmonary artery. Photomicrograph demonstrating a collection of foamy macrophages in the intima of this elastic pulmonary artery. There is no accompanying fibrosis or lymphocytic infiltration. Such lesions are visible macroscopically as bright yellow streaks in the arterial intima.

Fig 12.68 Pulmonary arterial hypertension: medial hypertrophy muscular pulmonary artery. Photomicrograph demonstrating media of this muscular pulmonary artery with increased thickness caused by muscle hypertrophy (and possibly hyperplasia). There is no intimal proliferation. (EVG)

Fig 12.69 Pulmonary arterial hypertension: cellular intimal proliferation muscular pulmonary artery. Photomicrograph demonstrating concentric proliferation of spindle cells in the intima of this muscular pulmonary artery with some deposition of myxoid ground substance. Some fibrin is present on the intimal surface. The muscular media is difficult to identify on this H&E section, but is not appreciably thickened. There is a surrounding inflammatory cell infiltration – not usually a feature of pulmonary arterial hypertension.

Fig 12.70 Pulmonary arterial hypertension: atrophic muscular pulmonary arteries. Explanted lung from a case of severe long-standing pulmonary arterial hypertension. Photomicrograph demonstrating muscular pulmonary arteries with very thin media with a mild degree of intimal fibrous thickening and resemble veins. Elsewhere there were plexiform lesions and severe intimal proliferation with luminal narrowing. These vessels are presumably distal to severe proximal stenosis and have thus become atrophic. This represents a pitfall in the assessment of vessels in long-standing disease. (EVG)

Fig 12.71 Pulmonary arterial hypertension: fibrinoid necrosis. Photomicrograph demonstrating a vessel with fibrinoid deposition and accumulation of foam cells; both indicators of severe vessel damage. Such lesions are not common, even in severe cases.

Fig 12.72 Pulmonary arterial hypertension: plexiform lesion. Photomicrograph demonstrating a muscular pulmonary artery with polypoid expansion with proliferation of spindle cells in the lumen to form tiny channels, some of which contain fibrin. Plexiform lesions tend to occur in supernumerary branches of large muscular pulmonary arteries.

Fig 12.73 Pulmonary arterial hypertension: dilatation lesion. Photomicrograph demonstrating, just to the left of center, a muscular pulmonary artery with severe narrowing of its lumen by fibroelastic tissue. To the left of it a branch of the vessel is expanded by a plexiform lesion. The whole complex is surrounded by multiple thin-walled vessels in the adventitial sheath of the parent artery – the so-called dilatation lesion. (EVG)

Fig 12.74 Pulmonary arterial hypertension: muscularization of arterioles. Photomicrograph demonstrating a small arterial vessel (arteriole) that would not normally be expected to have a well-developed muscle coat, showing a distinct layer of muscle between internal and external elastic laminae. (EVG)

Fig 12.75 Pulmonary venous hypertension. Photomicrograph demonstrating a pulmonary vein with remodeling of the wall with delineation of distinct internal and external elastic laminae and media composed of fibrous tissue and little muscle. The structure resembles an artery (albeit with a fibrous media), giving rise to the term arterialization of the veins. There is also concentric intimal collagenous thickening. (EVG)

Fig 12.76 Pulmonary venous hypertension. Photomicrograph demonstrating a small pulmonary vein without significant medial thickening but with prominent intimal fibrosis over a considerable length of the vessel. (EVG)

Fig 12.77 Veno-occlusive disease. Photomicrograph demonstrating a septal vein with arterialization of its media with intimal collagenous fibrous thickening and superimposed cellular intimal proliferation with near total occlusion of the vessel. The appearance is characteristic of veno-occlusive disease. (EVG)

Grading

• The Heath–Edwards grading system (Table 12.9) has been widely used in the past

not currently much clinically used although some clinicians may request it

• Generally accepted that with widespread intimal fibrous thickening the changes are irreversible

• Note that although changes may appear reversible this does not necessarily mean that the case is operable

Table 12.9 Heath–Edwards grading system for pulmonary hypertension in congenital heart disease

Grade 1	Medial hypertrophy of small muscular pulmonary arteries
Grade 2	Cellular intimal proliferation in muscular arteries
Grade 3	Concentric intimal fibrosis in muscular arteries
Grade 4	Plexiform lesions
Grade 5	Dilatation lesions and angiomatoid lesions
Grade 6	Fibrinoid necrosis

(data from Heath & Edwards 1958)

Specific entities are as follows.

PULMONARY ARTERIAL HYPERTENSION

• Commonest type seen in clinical practice

• Most cases (Adatia 2002) are

idiopathic

secondary to congenital heart disease

Congenital heart disease and pulmonary vascular disease

• Three main patterns

• Obstructive left-sided lesions with pulmonary venous hypertension (see below)

Fig 12.78 Pulmonary artery with low flow/low pulse pressure. Tetralogy of Fallot. In Tetralogy, in particular, there is a tendency to thrombosis. This thin-walled artery shows the effects of recanalized thrombus with multiple channels within the lumen.

PULMONARY VENOUS HYPERTENSION

• Secondary to any left-sided obstructive lesion including congestive cardiac failure

• If severe can be due to pulmonary vein stenosis

• Muscular pulmonary arteries show prominent medial hypertrophy

muscularization of arterioles

• Eccentric fibrous intimal thickening of pulmonary arteries

affects long stretches of the arteries

• No plexiform lesions

• Arterialization and medial thickening of pulmonary veins

intimal fibrosis

• Associated parenchymal changes frequent

interstitial fibrosis (Fig 12.79)

marked alveolar hemosiderin laden macrophages

osseous metaplasia

– very useful marker (Fig 12.80)

Fig 12.79 Pulmonary venous hypertension. Photomicrograph demonstrating lung parenchyma with thickening of the interstitium, intense capillary congestion and hemosiderin deposition in alveolar macrophages. The appearance is characteristic of increased pulmonary venous pressure, however caused; so-called congestive vasculopathy.

Fig 12.80 Pulmonary venous hypertension: osseous metaplasia. Photomicrograph demonstrating fibrosis of the interstitium and prominent hemosiderin deposition. In addition there are small nodules of bone. Osseous metaplasia is characteristic of longstanding congestion in the pulmonary venous bed.

Pulmonary vein stenosis

• Pulmonary hypertension usually presenting in the neonatal period

• Stenosis is not always detected on echocardiography

• Presence of a significant venous component should always alert to the possibility

Obstructed total anomalous pulmonary venous connection

• Not usually biopsied

• Very dilated bronchial veins may be confused with misalignment of pulmonary veins in alveolar capillary dysplasia (Becker et al 1971) (Fig 12.82)

Fig 12.82 Obstructed total anomalous pulmonary venous connection (TAPVC). A case of fatal obstructed anomalous venous connection. Photomicrograph demonstrating numerous dilated bronchial veins. The veins are so distended as to resemble pulmonary veins. Normal pulmonary veins were present in the interlobular septa. They could be mistaken for the misalignment of the pulmonary veins that accompanies alveolar capillary dysplasia. The secondary congestive changes in the interstitium (including lymphangiectasia) could further cause confusion. In making a diagnosis of alveolar capillary dysplasia TAPVC should always be excluded. (EVG)

ALVEOLAR CAPILLARY DYSPLASIA

• One of the commonest indications for neonatal lung biopsy

• Can only be diagnosed on biopsy

• Usually normal at birth

develop respiratory difficulty in the subsequent days and weeks

extreme difficulty in oxygenation despite ease of ventilation

death almost invariable

• Familial cases described

• Associated in some cases with other congenital abnormalities

Histopathological features

• Also medial hypertrophy in the muscular pulmonary arteries and muscularization of the arterioles

Fig 12.83 Alveolar capillary dysplasia with misalignment of the pulmonary veins. Photomicrograph demonstrating misalignment of the pulmonary veins. The interlobular septa were empty and the pulmonary veins ran with the muscular pulmonary arteries. The veins are the thin walled vessels accompanying the arteries in their collagenous sheaths. Note also the characteristic interstitial thickening and lymphangiectasia.

Fig 12.84 Alveolar capillary dysplasia. A section from the same case as Fig 12.83 above stained with antibody to cytokeratin. It demonstrates the thickened alveolar septa. The capillaries are just visible in the center of the septum, far removed from contact with the alveolar epithelium.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

• Syndrome characterized by

increased pulmonary vascular resistance

right-to-left shunting at the level of the oval fossa or the arterial duct

some die of the disease

• Very rare to have a biopsy to establish this diagnosis

• Multiple peripheral thick walled arteries

many are contracted

– endothelial cell nuclei projecting into the very constricted lumina almost occluding them (Fig 12.85)

Fig 12.85 Persistent pulmonary hypertension of the newborn (PPHN). Biopsy of a neonate with PPHN. Photomicrograph demonstrating some interstitial thickening. The section is stained with antibody to smooth muscle actin. It shows all the peripheral small muscular pulmonary arteries are contracted. Their lumina are narrow and the endothelial cells are cuboidal, projecting into the lumen.

CAPILLARY HEMANGIOMATOSIS

• Very rare in childhood

• Uncontrolled proliferation of pulmonary capillaries

may invade pulmonary parenchyma and bronchial and vascular walls (Fig 12.86)

• Diffuse alveolar hemorrhage

presenting clinically as hemoptysis

• Dyspnea

• Symptoms of pulmonary hypertension

• Lung transplant the only effective treatment

Fig 12.86 Pulmonary capillary hemangiomatosis. Photomicrograph of lung showing obliteration of the bronchial wall and lumen by capillary blood vessels. There is sparing of the pulmonary artery in the field but the pulmonary vein walls are affected. (EVG)

Histopathological features

• Often patchy changes

• Increase in capillaries in the interstitium

• Useful feature is the presence of excess capillaries in the walls of bronchi and blood vessels

• Heavy hemosiderin deposition

• Pulmonary venous and arterial hypertension

• CD31 staining highlights the increase in capillaries

• Caution: do not over-interpret collapsed parenchyma with its apparent increase in capillary density

PULMONARY LYMPHATIC DISORDERS

• Includes lymphangiectasia, lymphangioma and lymphangiomatosis

• Not always easy to separate into discrete entities

• Some confusion over nomenclature

Clinical features

• Associated pleural effusions

• Presents as dyspnea or hemoptysis

• Some have chromosomal disorders such as Trisomy 21, Turner’s syndrome, Noonan’s syndrome

• Radiologically there is increase in interstitial markings

Lymphangioleimyomatosis

• Rare

• May occur in teenagers with tuberous sclerosis

• Cysts

• Parenchymal proliferation of smooth muscle

• Pneumothorax

• May have bleeding

PEDIATRIC PULMONARY / THORACIC TUMORS

• Lung tumors as a group are uncommon in children as compared to adults

• Metastatic tumors outnumber primary tumors (benign and malignant combined) by a ratio of more than 4 : 1

• Primary benign tumors are commoner than malignant tumors by a ratio of approx 3 : 2

• Many rare tumors usually affecting other sites may occasionally affect the lung / thorax (see appropriate sections)

• Covered below are entities specific to pediatric surgical lung pathology

INFLAMMATORY MYOFIBROBLASTIC TUMOR

• 80% of benign lung tumors in children

• Most common in second decade

can occur in first year of life

• Cough, fever, hemoptysis, chest pain

• Recurrence rate of approx 14%

Macroscopic features

• Usually solitary lesion in the lung periphery

• Firm white cut surface (Fig 12.89)

may be gritty

Fig 12.89 Inflammatory myofibroblastic tumor. Right lower lobe of lung with pleura and diaphragm. There is marked thickening of the pleura over the diaphragmatic and lateral surfaces of the lung.

PLEUROPULMONARY BLASTOMA

• Malignant tumor of early childhood

true blastoma

• Associated with trisomy 8 in some cases

not specific

• May be multifocal

• May be associated with neoplasia in other family members

• Particularly common association with cystic nephroma

• Classified into types I, II and III based on macroscopic and microscopic features

Type I

• Least common (Hill et al 2008)

• Occurs in under 2-year-olds

median age 9 months

• May contain small nodules of immature cartilage

useful for diagnosis

• Treated by complete surgical excision with adjuvant chemotherapy

if incompletely excised, may recur as type II or III

Fig 12.91 Pleuropulmonary blastoma type 1. A one-year-old boy with a cyst in the right middle lobe. Subsequently he developed cysts in the left lung with similar morphology. Photomicrograph demonstrating a cyst with thin septa. Compressed normal lung is visible on the upper part of the picture. There is some fresh hemorrhage. The septa are covered by epithelium and, focally, have a cellular stroma.

Fig 12.92 Pleuropulmonary blastoma type 1. Photomicrograph demonstrating higher power view of a septum from Fig 12.91. There is a bland epithelial covering. The stroma is cellular. The constituent cells have hyperchromatic nuclei. There are numerous cells with obvious rhabdomyoblastic differentiation.

Type II

• Accounts for about 45% of cases

• Occurs in slightly older children than type I

median age 31 months

• Cystic, either grossly or microscopically with solid areas (Fig 12.93)

solid areas comprise malignant connective tissue elements (Fig 12.94)

– rhabdomyosarcoma

– blastema

– spindle cell sarcoma

cyst lining is benign

• May metastasize

Fig 12.93 Pleuropulmonary blastoma type 2. 3-year-old girl with left lung mass and pleural effusion. Solid and cystic mass 7cm diameter. Photomicrograph demonstrating cysts separated by thick cellular septa. The cysts contain proteinaceous fluid or blood.

Fig 12.94 Pleuropulmonary blastoma type 2. Photomicrograph demonstrating higher power view of Fig 12.93 showing hyperplastic but benign epithelium in the bottom right hand corner. The septal stroma is composed of undifferentiated cells with frequent mitotic figures.

PRIMARY PULMONARY CARCINOID

• Second in frequency to pleuropulmonary blastoma as a primary malignant lung tumor of childhood

• WHO classifies carcinoids into typical and atypical

based on mitotic count and presence of necrosis

• Intrabronchial or peripheral

Histopathological features

• Firm, well circumscribed solid yellow/tan tumors

• Usually endobronchial

• Uniform cells with rounded nuclei

typical endocrine appearance (Figs 12.95, 12.96)

may also see trabecular growth

• May be mild nuclear pleomorphism

• Atypical carcinoid defined by WHO as

greater than 2 mitotic figures /10 HPF (2mm²)

necrosis

• Note that superficial ulceration of an endobronchial carcinoid should not be interpreted as necrosis

necrosis should be in the center of the cell nests

• On biopsy because increased mitotic figures and necrosis may be focal, report biopsy as carcinoid

• Cytokeratins, chromogranin and CD56 positive

• Typical carcinoids have 10–15% lymph node metastasis at diagnosis

85–95% 10-year survival

• Atypical carcinoids have 40–50% lymph node metastasis at diagnosis

35% 10-year survival

Fig 12.95 Bronchial carcinoid. A 12-year-old girl with an endobronchial tumor that was resected. It measured 1.5cm in diameter. There was surface ulceration but no deep necrosis. Photomicrograph demonstrating nested and trabecular pattern with superficial erosion. There were very few mitotic figures and this tumor was classified as typical carcinoid.

Fig 12.96 Bronchial carcinoid. Photomicrograph demonstrating higher power view of Fig 12.95. The cells have very regular nuclei. There are no mitotic figures and there is no necrosis at the centers of the cell nests. These features, representative of the lesion as a whole, indicate that this is a typical carcinoid.

MUCOEPIDERMOID TUMOR

• Rare

• Occurs in children as young as 4 years but usually older

• Present with symptoms relating to bronchial obstruction

• Centrally located in the proximal bronchial tree

• Less than 5% metastasize to local nodes

• Generally indolent course

Histopathological features

• Endobronchial tumor (Fig 12.97)

• Yellow color

• Extension through bronchial wall

Fig 12.97 Mucoepidermoid carcinoma. 5-year-old girl with right pneumonectomy for tumor of the right main bronchus diagnosed on biopsy as mucoepidermoid carcinoma. The right main bronchus has been opened and the cut ends retracted to view the interior. The tumor is present in the main bronchus and is sessile and rounded. It comes close to, but does not involve, the resection margin of the bronchus. On section, the tumor extended into the bronchial wall but not through it.

Fig 12.98 Mucoepidermoid carcinoma. Photomicrograph of specimen in Fig 12.97. There are multiple dilated tumor glands containing eosinophilic mucus. Goblet cells are also evident. Smaller glandular structures without much mucus are also present. There are also intermediate cells in the background. The tumor ulcerated the mucosa and extended beneath intact mucosa. There was extensive calcification of the mucus.

Fig 12.99 Mucoepidermoid carcinoma. Photomicrograph of specimen in Fig 12.97. Non-keratinizing stratified squamous epithelium is present at the margins of the glandular structures. Calcification is evident at bottom left.