Pulmonary pathology in children [301536]

INTRODUCTION

Pulmonary pathology in children

Entities specific for children’s:

Congenital anomalies

Developmental abnormalities

Infant lung tumors

Entities posible to be find in children’s and adults:

Hemosiderosis

Bronchial/bronchiolar pathology

Lung infection

Metastatic lung tumors

Lung biopsy

Bronchoscopyc biopsy

Endobronchical biopsy

Transbronchial biopsy

Brushing biopsy

Bronchial aspirate and bronchoalveolar lavage

Biopsies obtained by transthoracic puncture

Pleural fluid

Pleural biopsy

Pulmonary fine needle aspiration biopsy

Lung biopsy

Surgical biopsy

Thoracoscopic

By thoracotomy

Processing

Microbiological examination !!!!!

[anonimizat] ± special stains ± [anonimizat]. Not suitable for biopsy.

Congenital acinar dysplasia;

Congenital alveolar dysplasia;

Alveolar capillary dysplasia.

[anonimizat] > 3 different genes

Sp-B + ABCA3 [anonimizat]-C [anonimizat], directly as idiopathic/familial fibrosis

Not to be confused with the infantile type of hyaline membrane disease that occurs in premature infants (<32 wk.) due to insufficient but with normal structure surfactant secretion.

Fig.1: Pulmonary alveolar proteinosis pattern (surfactant protein B, ABCA3 mutations) Mutations in the surfactant protein B gene and ABCA3 gene typically result in a [anonimizat], [anonimizat].

Fig.2: Chronic pneumonitis of infancy pattern (surfactant protein C mutation) Mutations in surfactant protein C result in variable morphology depending in part on age at diagnosis. [anonimizat] a [anonimizat], [anonimizat], [anonimizat].

Congenital cystic lung

Cystic thoracic lesions and biopsies are frequently found in children. [anonimizat] a radiologic intrathoracic cyst.

Table 1:

Intrathoracic cystic lesions in the newborn and child

Bronchogenic Cyst

Abnormal development of the bronchial tree

In mediastinum (central cysts) [anonimizat] (peripheral cysts)

Bronchial wall structure

Fig.3: Bronchogenic cyst. The lesion recapitulates a [anonimizat].

[anonimizat] – [anonimizat], segmental, or subsegmental distribution. Isolated bronchial atresia typically presents in older children or adolescents with dyspnea, recurrent pneumonia, wheezing, or as an incidental finding on a chest x-ray. It is most often segmental and commonly involves the left upper lobe, but also occurs in the right upper or lower lobes. The widespread use of in utero ultrasound has resulted in early identification and surgical excision, making these lesions now more common in infants.

Bronchial atresia results in a cystic mucus-filled central airway (mucocele), often producing a bulge or palpable mass lesion near the hilum. The parenchyma within the distribution of the atretic bronchus is hyperinflated and often shows dilated, mucus-filled branching airways. If the atretic bronchus is large, it may form a nodular focus of cartilage at the hilum of the lobe.

Extralobar Sequestration

Congenital malformation possible to be diagnosed in utero

Accesory pulmonary tissue with a pleura of its own and outside lung pleura unattached to the respiratory tree, normally located in the mediastinum, but possible retroperitoneal or abdominal cavity.

Intralobar sequestration

Area of pulmonary tissue not connected to normal bronchial tree, usually with a separate abnormal vascularization.

Sometimes the area presents cystic dilatation of airways.

The alveolar spaces of sequestration communicate with alveolar spaces of normal lung with possible extension of inflammations from normal to sequestration resulting in relapsing pneumonias in children or even adults.

Differential diagnosis – Enterocysts

Mediastinum or intrapulmonary

Remains of primitive digestive tract

Nonrespiratory epithelium (gastric, intestinal or even areas with squamous epithelium)

CCAM – Congenital cystic adenoid malformation

Stocker Classification – 1978 = obsolete

Definition: Focal developmental malformation of the lung usually forming a single large, often multiloculated, cystic structure

Incidence

Uncommon, but commonest of the cystic maldevelopments

Morbidity and Mortality

Variable, from asymptomatic to large, space-occupying lesions producing compression and rarely hypoplasia of the remaining lung

Surgical excision is usually curative

Clinical Features

Increasing respiratory distress usually in the first week, but sometimes delayed

Radiologic Features

In utero – hyperlucent region

Post-natally – single, often multilocular, air-filled cystic lesion, enlarging, often with mediastinal shift

Cannot be separated radiologically from low-grade cystic pleuropulmonary blastoma or intrapulmonary lymphangioma

Microscopy

The wall of the cyst shows areas of continuity between the lumen and adjacent smaller alveolar duct-like structures and alveoli. Focal mucigenic epithelium resembling gastric foveolar epithelium is a frequent finding.

Prognosis and Treatment

Surgical excision

Rarely, late development of bronchioalveolar carcinoma

Primary pulmonary lymphatic disorders

Pulmonary Lymphangiectasia

Lethal in utero or in the first hours after birth – not suitable for biopsy examination

Pulmonary lymphangiomatosis

Lymphangiomas

Pulmonary lymphangiomatosis

Diffuse proliferation of pleural and septal lymphatic vessels.

Slow but unstoppable degradation of respiratory function

Transplantation – is the only possible treatment.

Cystic lymphangiomas

Mediastinum or intra pulmonary.

Primary ciliary dyskinesia

Rare, AR, sinusitis, otitis, relapsing pneumonias ± situs inversus. Presentation is usually in childhood, although some cases are not detected until adulthood, particularly when associated with male infertility.

Bronchiectasis and progressive lung disease

Light microscopic examination of unstained wet preparations using fresh ciliary brushings and/or biopsies is commonly used as a screening tool. Lack of coordinated and rhythmic movement of cilia may reflect primary ciliary dyskinesia, but may also be secondary to other factors

Cystic fibrosis

The most common cause of chronic pulmonary distress – variable severity

Respiratory tract obstructions, bronchiectasis, recurrent infections

Generates pneumothorax, hemoptysis, pulmonary hypertension and right ventricle hypertrophia.

Fig.4: Bronchiectasis in cystic fibrosis

Cystic fibrosis is a systemic disease with significant pulmonary component. It is the most common cause of chronic lung disease in children. Severity of lung disease varies with each patient, typically observed airflow, bronchiectasis and recurrent infections. This autosomal recessive disorder caused by heterozygous mutation of the cystic fibrosis transmembrane gene regulator of chromosome 7. Mutation leads to loss of transporter function by blocking chloride channels chloride ions passing through the respiratory epithelium and decreased water content and sodium luminal mucus. Will result in a sticky mucus that cause chronic infections with bacterial colonization (particularly colonization with Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus and Haemophilus influenzae). Airways may also be colonized by fungal organisms (20%), particularly Candida and Aspergillus, which in some cases manifests as allergic bronchopulmonary fungal disease (10%). Pulmonary complications include pneumothorax, haemoptysis, pulmonary hypertension and right ventricular hypertrophy (heart lung). Ductal secretions blocking other organs that lead to organ failure, particularly pancreatic dysfunction (fat malabsorption, malnutrition, diabetes). Other manifestations include meconium ileus in newborns, and focal biliary cirrhosis in male infertility. Although genetic tests are available for common CFTR mutations, sweat test remains the main method of diagnosis, demonstrating high levels of sodium and chlorine. Pathologist changes are nonspecific (excluding meconium ileus and changes in the pancreas) and are only used as an argument for clinical diagnosis, laboratory tests. Pathologists can make the diagnosis only when have access to autopsy examination of all organs.

The lung in cystic fibrosis have progressive change from stasis secretion clearance leading to abnormal respiratory infections, sudden, local inflammation and immunological alterations leading to recurrent injury to the airway walls with possible destructions of smooth muscle and cartilage. Partial replacement by a respiratory mucosal tissues grain and vascular changes due to chronic infections will favor the emergence hemoptysis. Bronchiectasis is the marker key is generated for cystic fibrosis and mucus plugs and secondary infections.

We have at least 100 cases diagnosed autopsy (in 30 yrs.) but none on lung biopsy, although it is possible that some of the bronchiectatic lessions diagnosed on surgical specimens have had this substrate. But the diagnosis was suspected in at least 12 biopsies (in the last 10 years) of which 2 liver and duodenal biopsy’s.

“Congenital” bronchiectasis

Not a malformation. Means that appears early in life

It’s always a secondary lesion.

Congenital diseases:

Cystic fibrosis

Intralobar sequestration

Congenital immunodeficienties – chronic inflammations

Primary ciliary dyskinesia

Williams-Campbell syndrome – congenital absence of cartilaginous bronchial wall

Mounier-Kuhn syndrome (congenital traheobronchomegaly), – connective tissue disease

Post infectious – at any age

Post obstructive

Foreign body aspiration – children

Tumors

Other

Rheumatoid arthritis, lupus, IBD, post transplantation

DEVELOPMENTAL ABNORMALITIES

Pulmonary hypoplasia

Pulmonary hyperplasia

Interstitial pulmonary glicogenosis

Neuroendocrine cellular hyperplasia of infancy

Persistent pulmonary hypertension of the newborn

Complications of prematurity and its therapy

Hyaline membrane disease (HMD)

Bronchopulmonary dysplasia (BPD), and

Pulmonary interstitial emphysema (PIE),

Table 2:

Conditions and Anomalies Associated with Pulmonary Hypoplasia

To define pulmonary hypoplasia, the simplest method is the radial alveolar count, which is the number of alveoli transected by a perpendicular line drawn from the center of a respiratory bronchiole to the nearest septal division or pleural margin. The radial count in a full-term infant should average 5 alveolar spaces. In pulmonary hypoplasia there is a reduction of alveolar spaces for gestation age, which is often accompanied by prominence of the bronchovascular structures and a widened interstitium. Widened alveolar ducts, enlarged airspaces, and dilatation of the subpleural alveoli that may resemble cysts characterize deficient alveolarization of postnatal onset.

Interstitial pulmonary glicogenosis

Other names: cellular interstitial pneumonia / histiocytic pneumonia

newborn, infants < 6 months

Pathognomonic:

Proliferation of septal mesenchymal, rich in glycogen, cells

Isolated disease or part of another underlying lung disease (bronchopulmonary dysplasia)

Clinical:

Deterioration of respiratory function occurs after an initial normal period.

Patients often require prolonged mechanical ventilation and supplement of oxygen.

Although these children may remain symptomatic for a long period of time (up to 18 months after the diagnosis), clinical course is marked by a further improvement

Mortality is rare unless the patient has an underlying lung disease due to prematurity.

Microscopy:

Lung biopsy shows varying degrees of septal expansion with fuziforme cells.

Usually the distribution is focall

Inflammation as reactive change, and fibrosis are absent.

PAS coloration indicates a labile PAS-positive material in the cytoplasm of these interstitial cells rich in glycogen.

Since glycogen preservation is influenced by the use watery fixative agent (eg. 10% formic acid), these changes are difficult to be proved in a routine exam.

The accumulated cells within the alveolar septae uniformly stain positive for vimentin. In normal conditions, one can see vimentin-positive cells around vessels, but not in alveolar walls.

Because pulmonary interstitial glycogenosis carries a favorable prognosis, it is critical to distinguish it from other pediatric interstitial lung diseases that are associated with high morbidity and mortality. PIG/infantile cellular interstitial pneumonitis has sometimes been confused with chronic pneumonitis of infancy. Microscopically, the presence of uniform, prominent type II cells, some degree of PAS-positive material within air spaces, accumulation of macrophages, and occasional cholesterol clefts favors the diagnosis of chronic pneumonitis of infancy. Lung disease is not usually a prominent feature of storage diseases, but significant pulmonary involvement with accumulation of stored material can be seen in both air spaces and the interstitium in Gaucher disease, Niemann-Pick disease, Fabry's disease, Hermansky-Pudlak syndrome, infantile GM1 gangliosidosis, Krabbe disease, Pompe disease, and Farber's disease. Unlike PIG, the accumulating cells are histiocytes and should stain for macrophage markers.

Short-term pulse corticosteroids have been shown to be beneficial in patients with or without preexisting lung disease. A good response has also been reported with chloroquine. In infants without complications of prematurity, long-term follow-up has demonstrated a favorable outcome including normal growth and development and no significant residual pulmonary symptoms.

NEUROENDOCRINE CELLULAR HYPERPLASIA OF INFANCY

Other names: Persistent tachypnea of the newborn and chronic idiopathic bronchiolitis of the newborn

Disruption ratio of ventilation / perfusion

Clinical:

Show extreme tachypnea, hypoxia.

Installation of symptoms usually occurs under the age of one year, although the age at which lung biopsy practice is often delayed.

Despite the apparent severity of the disease based on clinical symptoms, lung biopsies appear free of any diagnostic disease process, although most show minor and nonspecific abnormalities involving the distal airways. A mild periairway lymphocytic infiltrate is often seen but not prominent.

Bombesin has been shown to be the most sensitive immunostain for detecting increased neuroendocrine cells in this disorder. Serotonin has also been shown to be effective. Neuron-specific enolase, calcitonin, synaptophysin, and chromogranin are much less reliable in demonstrating this increase. Immunohistochemical assessment of this disorder requires an adequate biopsy with at least 10-15 evaluable airways.

Neuroendocrine cell number is altered in several pediatric conditions including bronchopulmonary dysplasia, chronic bronchiolitis, cystic fibrosis, asthma, mechanical ventilation, and sudden infant death syndrome. Unlike most of these conditions, the lung biopsy in in this condition should be free of diagnostic abnormalities characteristic of a known pulmonary process, such as architectural disruption (seen in bronchopulmonary dysplasia) or changes of chronic lung injury (seen in chronic bronchiolitis, cystic fibrosis, asthma, or mechanical ventilation), including significant inflammation and prominent airway damage.

Although patients may be symptomatic and often require supplemental oxygen for months to years, their clinical condition improves over time. Symptoms are not reversible with bronchodilators, corticosteroids, hydroxychloroquine, and azathioprine. There have been no deaths reported, and no patients have progressed to respiratory failure or required lung transplantation. Patients may remain symptomatic with respiratory infections or exercise.

PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Definition

Syndrome associated with persistent postnatal elevation of pulmonary vascular resistance, characteristic of the fetal circulation

Primary and secondary forms of PPHN exist

Incidence

Estimated prevalence 1.9 per 1000 live births

Mortality

Good survival in secondary PPHN

High mortality (60%) in patients with primary PPHN

Gender and Age Distribution

Term or post-term infants

Slight male predominance

Clinical Features

Onset of symptoms (cyanosis, respiratory distress) at or shortly after birth

Pulmonary hypertension

Right-to-left shunt, at ductus arteriosus or foramen ovale

Prognosis and Therapy

Supplemental oxygen is needed, as well as high frequency oscillatory ventilation (HFOV) or extracorporeal membrane oxigenation (ECMO) in patients with significant respiratory distress and CO2 retention

Nitric oxide may also be helpful

Microscopic Findings

Muscularization of small pulmonary arteries with reduction of luminal diameters

Neomuscularization of precapillary intra-acinar vessels

Thickening of connective tissue sheaths around vessels

Immunohistochemical Features

Smooth muscle actin highlights the smooth muscle hyperplasia of small vessels

Fig.5: Medial thickening of small pulmonary arterys and the increased adventitia around this vessels

COMPLICATIONS OF PREMATURITY AND ITS THERAPY

Hyaline membrane disease

Low quantity of surfactant leads to an insufficient surface tension in the alveoli during the expiratory, leading to atelectasis, decreased gas exchange and severe hypoxia with acidosis.

Chronic lung disease of newborn

Bronchopulmonary dysplasia

Interstitial emphysema

Bronchopulmonary dysplasia

Secondary to pulmonary diseases that requires administration of concentrated O2 and prolonged mechanical ventilation:

Hialine membrane disease

Pneumonia / sepsis

Meconium aspiration

Non-lethal pulmonary hypoplasia

Cyanogen heart malformations

Phases of Classic Bronchopulmonary Dysplasia

Our experience

15 surgical lung biopsy in 10 years

2 with classic bronchopulmonary dysplasia

Boys (6 and 9 year old)

Clinical diagnosis of chronic pneumonia

Fig.6: Alveolar spaces with partialy incorporated hyaline membranes and enlaged fibroblastic intertitial

In the post-surfactant era, the lungs of infants with BPD, termed “new” BPD, show less fibrosis and more uniform inflation. However, alveoli remain simplified and enlarged, reflecting an interference with postnatal septation. Only occasionaly, cases of “classic” acute BPD is still possible to be seen.

Pulmonary interstitial emphysema

Appears in situations requiring assisted ventilation with positive pressure in case of reduced lung compliance (dysplasia).

Associated to adult type Respiratory Distress Syndrome

Other:

meconium aspiration,

perinatal asphyxia

neonatal sepsis.

Acute (lasts less than a week)

No biopsy

Persistent – eventualy biopsy

By compresion of the neighboring lung tissue and vascular structures, his presence may compromise the existance of newborn baby alredy sufering from other critical diseases.

Our experience

Only autopsic

6 cases în 30 yrs.

Fig.7: Interstitial emphisema.

Lung Neoplasms in Infants and Children

Metastases

Myofibroblastic inflammatory tumor

Carcinoid

Rare tumors:

Pleuropulmonary blastoma

Salivary gland-type neoplasms

Conventional types of lung carcinoma

Sarcomas

Epstein Barr virus-associated smooth muscle tumors

Hamartoma

Granular cell tumor

Leiomyoma

Bronchial chondroma

Teratoma

Our experince

In 10 yrs, 4 tumors

1 Askin tumor of the thoracic wall infiltrating the lung

1 limfoma – diagnosed on pleural fluid smear

2 nonspecified malignant tumors – pleural fluid smears

1 clinicaly with pulmonary metastases

1 without tumoral clinical history.