Pediatric Pathology
Dan Lodge-Rigal, MD
Outline
Pathology of Intrauterine Growth and Development
Intrauterine Growth Restriction
Problems of Immaturity
Congenital Malformations and Teratogenesis
Pathology of the Neonate
Respiratory Distress Syndrome
Hydrops and Hemolytic Disease of the Newborn
Metabolic and Genetic Disorders
Cystic Fibrosis
Phenylketonuria
Galactosemia
Sudden Infant Death Syndrome
Pediatric Neoplasia
Reading:
Robbins Basic Pathology Chapter 6 , pp 223-228 (metabolic diseases); 245-263 (pediatric
diseases)
Clinical Lab Source: L/S ratio and PG: pg.346
Phenylalanine: pg.417
Sweat Chloride: pg.504
Online case: Young girl with a cough, case 20 on both the website and disc.
Disorders of Intrauterine Development
Disorders of Growth and Maturation
Assessing intrauterine growth and development:
Correlation of Birth Weight with Gestational Age
Intrauterine Growth Restriction (IUGR)
Etiology :
Fetal
Placental
Maternal factors
symmetric versus asymmetric IUGR
Complications of Immaturity
Specific Organ Systems:
Lungs:
Brain:
Liver:
Abnormalities of Form: “Birth Defects”
Incidence
Clarification of concepts: Congenital Malformations (anomalies)
Malformations
Deformations
Disruptions
Malformation Sequences and
Syndromes
Potter’s Sequence
Etiologic Factors and
Teratogenesis
Causes of Congenital Malformations:
Genetic
Environmental
Multifactorial
Unknown
Importance of Timing and Targets
Molecular Events:
Birth Injuries
Risk factors:
Common injuries:
Perinatal Infections
Ascending infection:
Hematogenous (trans-placental) infection:
Respiratory Distress of the Newborn
Lung Development and Maturation
Surfactant: Lecithin and Sphingomyelin
Factors effecting surfactant maturation
weeks gestation
Respiratory Distress Syndrome
Clinical Features
respiratory distress: tachypnea, grunting respirations
hypoxemia, cyanosis
diffuse granular infiltrates on CXR
risk factors: prematurity, maternal diabetes, cesaerean section
Pathogenesis
surfactant deficiency
hypoxemia
Pathologic Features
Gross:
heavy lungs (don’t float)
Microscopic:
hyaline membranes in distal airspaces
later: organization and fibrosis
Sequelae of RDS
1)
2)
3)
Consequences of therapy:
1)
2)
Fetal Hydrops
Definition:
Causes
Immune
1)
2)
3)
Non-Immune
1)
2)
3)
4)
Pathogenesis:
EFFLUX of fluid out of vasculature due to some combination of:
increased hydrostatic pressure
decreased oncotic pressure
damage to vascular integrity
Pathology:
Generalized edema:
Hepatomegaly
Pathology of underlying disorder. i.e. TORCH infection, parvovirus
Hemolytic Disease of the Newborn
Etiology: maternal/fetal blood antigen incompatibility (Rh, ABO, other)
Pathogenesis: sensitization and antibody production
Immune hemolysis
Anemia and hyperbilirubinemia of fetus and
newborn
sequelae:
Cardiac failure and hydrops
Kernicterus
Interventions
Prevention:
Rh-immunoglobulin (RhoGam) to PREVENT SENSITIZATION
Monitoring hemolysis:
amniocentesis and cord blood sampling
bilirubin in the amniotic fluid: change in optical density (OD)
Selected Metabolic Diseases
Phenylketonuria
Definition and Incidence
Pathogenesis
Diagn
osis
and
Screen
ing
Treat
ment
Galactosemia
Definition and Incidence
Pathogenesis
Diagnosis and Screening
Treatment
Cystic Fibrosis
Definition:
Incidence:
Pathogenesis:
Defect in membrane chloride channel
protein
Cystic Fibrosis Transmembrane Regulator
Protein or CFTR
Effects of abnormal CFTR
Damage to gland parenchyma (pancreas, salivary epithelium, bile ducts)
and airway obstruction and inflammation
Chronic respiratory infection: pseudomonas auruginosa (mucoid)
Burkholderia cepacia
Sequelae of chronic lung disease:
1)
2)
Genetics of Cystic Fibrosis
CFTR gene located on long arm of Chromosome 7
most common mutation involves phenylalanine codon at position 508
(delta 508)
other mutations documented, can have variable phenotypic expression
Pathologic Features:
Lungs:
Pancreas:
Liver:
GI:
Other
Diagnosis and Clinical Course:
Median survival: 36 years, death from infection, respiratory failure
Treatment:
Sudden Infant Death Syndrome
Definition
The sudden death of an infant under one year of age which remains unexplained after a thorough
case investigation including a COMPLETE AUTOPSY, DEATH SCENE INVESTIGATION,
and REVIEW OF CLINICAL HISTORY
Incidence and Epidemiology
8000 deaths/year in US attributed to SIDS; most common cause of postnatal mortality
Most cases occur in infants 2-4 months of age
Prematurity is strongly correlated
Most cases occur during sleep, but some cases are witnessed
Variety of “risk factors” described involving features of the mother, home environment, prior
family history of SIDS
per 1000 live births
Pathologic Features
The crucial finding is an ABSENCE of a potentially LETHAL abnormality
Common findings in SIDS include:
pleural/pericardial petechiae
astrogliosis of brainstem
persistent hepatic hematopoiesis
Theories of Pathogenesis
cardiovascular abnormality (conduction system)
neuroendocrine immaturity
metabolic abnormality
sleeping position: prone vs supine “smothering”
Pediatric Neoplasia
Pediatric versus Adult Tumors
most common pediatric neoplasms involve the hematopoietic system
some pediatric tumors associated with abnormal development
spontaneous regression
familial tendency, genetic basis
Benign Tumors
Hemangioma
Lymphangioma
Teratomas
Malignant Neoplasms
Neuroblastoma
Cell of origin:
Common sites:
adrenal medulla (25-30%)
sympathetic chain
brain
Gross: variably sized, hemorrhagic tumors
Microscopic:
primitive small cells with high N/C ratio, mitoses
pseudorosettes
+/- neuronal differentiation
may show differentiation into benign neoplasm, or regression
Cytogenetics:
deletion of short arm of chromosome 1 (del 1)
associated with poor prognosis
Oncogene:
n-myc oncogene amplification
(double minutes or homogeneously staining regions)
Biogenic amine production: urinary HVA, VMA
Prognosis:
Favorable features:
1)
2)
3)
4)
5)
Unfavorable features:
1)
2)
3)
4)
5)
Treatment
Retinoblastoma
Cell of origin:
Age of onset:
Site: orbit, solitary vs bilateral/multifocal
Inherited form: 6-10% are familial (most bilateral)
Gross:
nodular retinal mass
occasional extraocular spread, metastasis
Micro:
small primitive cell, high N/C ratio
hemorrhage and necrosis common
rosette formation
Genetic abnormality:
Retinoblastoma gene (Rb) on long arm of 13
Other clinical features:
1)
2)
3)
Wilms Tumor
Cell of origin: primitive nephrogenic cell
Age of onset:
Site:
Inherited forms:
WAGR syndrome:
Wilms tumor, aniridia, genital anomalies, retardation
autosomal dominant or sporadic deletion of 11p13 (WT-1)
Denys-Drash Syndrome:
gonadal dysgenesis, nephropathy
majority develop Wilms tumor associated with WT-1
Beckwith- Wiedemann Syndrome:
organomegaly
hemihypertrophy
renal cyst
adrenal cytomegaly
genetic abnormality involving 11p15.5 (WT-2)
Gross:
Large fleshy mass in kidney
___ % bilateral
Micro:
3 elements:
1)
2)
3)
Clinical presentation:
1)
2)
Treatment
Other Solid Tumors
Concept of “Small Round Blue Cell Tumors of Childhood”
PEDIATRIC PATHOLOGY
For All Budding Pediatric Pathologists
Study Questions
Fetal Growth and Maturation /Congenital Anomalies
1. What are the crucial time periods of development for teratogenesis
2. Distinguish Malformation, Deformation, Disruption
3. What is the difference between symmetric vs asymmetric growth retardation
4. What are the 3 major areas to consider in the causality of intrauterine growth
restriction? Give a couple of examples of factors from each area.
5. What is a sequence? What are sequelae of the oligohydramnios (Potter) sequence
6. How does retinol impact the expression of homeobox genes such as the HOX genes.
7. What are the major predisposing factors for Respiratory Distress Syndrome (RDS)
8. Describe the pathophysiologic sequence of events in development of hyaline membrane
disease
9. What are hyaline membranes made of? Why do they form?
10. What are 2 complications of RDS? What is 1 potential complication from therapy of RDS?
11. Give one example of a clinical symptom/sign in a neonate which would be reflective of
underlying organ immaturity (other than RDS)
12. What is a Caput Succedaneum?
13. Why does Hemolytic Disease of the Newborn typically NOT affect the firstborn child?
14. When is RhoGam given? Why?
15. What are 3 causes of NON-IMMUNE HYDROPS?
16. What is the enzymatic defect in Phenylketonuria (PKU). What are the typical clinical
findings?
17. What is benign hyperphenylalaninemia (say that 3 times real fast!)? Maternal PKU?
18. What is the most common enzymatic defect in galactosemia? What urine test is
might be an initial indicator of the disease?
19. What organs are involved in galactosemia?
20. Describe the CFTR protein, its function, and the consequences of abnormal CFTR function
in sweat glands and in the lungs.
21. What organisms are commonly implicated in lung infections in patients with cystic fibrosis
(CF)?
22. Describe examples of different types of CFTR mutations. What is the most common detected
mutation?
23. What are the major organs affected by CF other than the lungs? What is congenital absence
of the vas deferens?
24. In an infant presenting with intestinal obstruction, CF might be in your differential diagnosis.
Why?
25. What is our current understanding of the etiology of SIDS?
26. Why is an autopsy appropriate for every unexpected infant death?
27. What are 2 disorders recently found to underly a small number of deaths previously
attributed to SIDS?
28. Give an example of a pediatric neoplasm, where there appears to be a close link with
developmental abnormalities.
29. What are some favorable prognostic features in neuroblastoma? Unfavorable?
30. What is the most common site for neuroblastoma?
31 What is unusual about Stage IVs neuroblastoma?
32 What percentage of Wilm’s Tumors are bilateral.?
33 Name 2 genetic syndromes associated with Wilm’s tumor.
34 True or False: The vast majority of cases of sporadic Wilm’s tumor have mutation in either
the WT-1 or WT-2 gene or both.
35 What is the most common pediatric malignancy?