Update on the Pathology of Diffuse Lung Disease in Infants and Children

1. Update on the Pathology of Diffuse Lung Disease in Infants and Children Megan K. Dishop MD Associate Professor Department of Pathology Children’s Hospital Colorado University of Colorado School of Medicine Denver, Colorado, USA megan.dishop@childrenscolorado.org

3. New Developments in Pediatric Diffuse Lung Disease • European Respiratory Society Task Force • Clement A, ERS Task Force. Task force on chronic interstitial lung disease in immunocompetent children. Eur Respir J 2004; 24:686-697. • Children’s Interstitial Lung Disease Network • Recommendations for handling of pediatric lung biopsy • Langston C, Patterson K, Dishop MK, for the chILD Pathology Co-operative Group. A protocol for the handling of tissue obtained by operative lung biopsy: Recommendations of the chILD pathology co-operative group. Ped Dev Pathol 2006; 9: 173-80. • Classification of pediatric lung disease, based on lung biopsy • Deutsch GH, Young LR, Deterding RR, Fan LL, et al. Diffuse lung disease in young children: Application of a novel classification scheme. Am J Respir Crit Care Med 2007; 176: 1120-1128. • Langston C, Dishop MK. Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatr Dev Pathol 2009 Nov-Dec; 12(6): 421-437.

4. Classification of Diffuse Lung Disease in Children I. DISORDERS SPECIFIC TO INFANCY II. DISORDERS OF THE NORMAL HOST Infectious and post-infectious Aspiration, Environmental agents (Hypersensitivity pneumonia, Inhalation) III. DISORDERS RELATED TO SYSTEMIC DISEASE Autoimmune, collagen-vascular Metabolic, storage disease Sarcoidosis, Langerhans cell histiocytosis IV. DISORDERS OF THE IMMUNOCOMPROMISED HOST Opportunistic infections Chemotherapy, drug or radiation effects Rejection V. VASCULAR DISORDERS MIMICKING INTERSTITIAL DISEASE Pulmonary hypertension, Lymphangiectasia, Congestive changes Related to congenital heart disease

5. Classification of Diffuse Lung Disease in Children I. DISORDERS SPECIFIC TO INFANCY A. Diffuse Developmental Disorders Alveolar Capillary Dysplasia/Misalignment of Pulmonary Veins Acinar Dysgenesis Congenital Alveolar Dysplasia B. Surfactant Dysfunction Disorders SP-B, SP-C, ABCA3, other C. Pre- and Post-natal Growth Abnormalities Pulmonary Hypoplasia Chronic Neonatal Lung Disease Chromosomal disorders D. Reactive and possibly reactive disorders Pulmonary Interstitial Glycogenosis (PIG) /Infantile Cellular Interstitial Pneumonia (ICIP) Neuroendocrine Cell Hyperplasia of Infancy (NEHI)

6. INFANTS OLDER CHILDREN AND ADOLESCENTS

7. Alveolar growth abnormalities *

8. Bronchopulmonary dysplasia

9. Chronic neonatal lung disease (“New” BPD) Normal infant lung

10. Preterm, Chronic neonatal lung disease Term, Pulmonary hypoplasia Term, Down syndrome (Trisomy 21) Term, Pulmonic stenosis

11. Update in Pediatric Diffuse Lung Disease: Selected Topics • Pulmonary interstitial glycogenosis (PIG) • Neuroendocrine cell hyperplasia of infancy (NEHI) • Alveolar Capillary Dysplasia • Genetic Disorders of Surfactant Metabolism

12. Pulmonary interstitial glycogenosis

13. Pulmonary Interstitial GlycogenosisHistology Diffuse expansion of the interstitium by glycogen-laden (PAS+) mesenchymal cells (vimentin +; negative for epithelial, macrophage and leukocyte markers) vimentin

14. Cytoplasmic Glycogen Cytoplasmic Glycogen Pulmonary Interstitial GlycogenosisElectron Microscopy • Interstitial cells contain monoparticulate glycogen • ?Abnormality in cytodifferentiation of interstitial mesenchymal cells ER ER PA-SM METHOD TANNIC ACID METHOD

15. Pulmonary Interstitial Glycogenosis • Histologic features of patchy PIG found in 26% of growth abnormalities (postnatal/BPD) Growth + Patchy PIG Growth + Patchy PIG

18. Pulmonary Interstitial GlycogenosisClinical • Presents in preterm and term infants within first month of life (most have symptoms at 1 day of age) with tachypnea, hypoxemia and diffuse interstitial infiltrates • Favorable prognosis with mild symptoms long-term • Benefit of pulse steroids Schroeder et al., Chest 1992 Canakis et al., Am J Respir Crit Care Med 2002

19. Neuroendocrine cell hyperplasia of infancy

20. NEHI • Clinical ILD syndrome • “Persistent tachypnea of infancy” • Mean age, 3.8 months • Term infants • Tachypnea, crackles, retractions, hypoxia • Cough is not a prominent feature • Patients rarely wheeze • CXR: Hyperexpansion and interstitial markings • HRCT: Areas of ground glass

21. Bombsin Bombesin Bombesin

22. DIAGNOSTIC CRITERIA 1. NECs are present in at least 75% of bronchioles. 2. NECs are at least 10% of respiratory cells. 3. NEBs are large. 4. Other alveolar, interstitial, vascular, and airway disease is excluded. 5. Appropriate clinical and radiographic context.

23. Neuroendocrine cell hyperplasia of infancy • Other causes of NEH excluded: • BPD, acute lung injury, altitude, smoke exposure, CF, SIDS • Outcome • Usually stable or slow symptomatic improvement over months to years • No mortality • Poor response to bronchodilators or corticosteroids

24. Alveolar capillary dysplasia

25. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins • Described in 1981 • Initially diagnosed only at autopsy • Now, biopsy also • Cause of persistent pulmonary hypertension in the newborn (PPHN) • Infants at term or near-term • Present in first few days of life - pulm htn • May respond initially but not sustained • Most die within one month • Rare cases with prolonged survival to 6 months

26. Figure 8 C06-535 he9

27. Figure 9 C05-248 he5

29. ACD-associated malformations Heart HLHS, ASD, AVC, TAPVC, CoAo, MV/TV malf Lungs Bilobed lungs Liver AV malformation, absent GB Kidney UPJ obstruction, atresia membranous urethra, hydronephrosis GI Hirschsprung, intestinal malrotation, imperforate anus Skeletal Butterfly vertebrae Skin Portwine stain

30. Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins • Familial cases • sibling pairs • Association with other anomalies • About 50% of cases • GI, GU, Cardiac, Limb anomalies • No consistent pattern • Lethal • Typically within weeks • Rare cases of prolonged survival to 6 months • 2009: FOXF1 gene or FOX transcription factor gene cluster deletions/mutations • 2010: Paternal imprinting • 2013: Regulation of FOXF1 by long non-coding RNAs • 2014: Misaligned veins appear to be intrapulmonary shunt vessels between pulmonary and bronchial circulation

31. Genetic disorders of surfactant metabolism

32. Surfactant Dysfunction Disorders • Etiology • Abnormal surfactant protein • SP-B (SFTPB, chr 2p12-p11.2, AR) - 1993 • SP-C (SFTPC, chr 8p21, AD) - 2001 • Surfactant transport • ATP binding cassette transporter, ABCA3 (chr 16p13.3, AR) - 2004 • Surfactant recycling • GM-CSF receptor alpha chain – 2008 • GM-CSF receptor beta chain - 2011 • Regulation of surfactant protein production • NKX2.1/TTF1 deficiency - 2009

33. CXR: bilateral hazy opacities

34. Chest CT: Diffuse granular ground glass density

35. S02-7073 he 20x 2

37. PAS PAS stain

39. ABCA3 Mutations

40. Summary of features of ABC transporters

43. ABCA3 Normal

44. Pulmonary alveolar proteinosis SP-B mutation Figure 1 C01-141 pap he 20x 2

45. Normal SP-B deficiency

46. “Chronic pneumonitis of infancy” pattern 7 month old with known SPC mutation

47. 15 year old with chronic lung disease. Diagnosed with “DIP” at age 2.

49. NSIP pattern and pulmonary fibrosis in SPC disease

50. 2 month old girl transplanted for surfactant dysfunction disorder. Diagnosed on lung biopsy at 30 days of age