Pediatric Pathology Flashcards

Question

Biliary Atresia

Answer 1

* Complete obstruction of the lumen of the extrahepatic biliary tree within the first three months of life. * Most frequent cause of chronic cholestasis in infants and children **Clinical forms ** Embryonic or fetal type (20%) * – Due to aberrant intrauterine development of the extrahepatic biliary tree * – early onset neonatal cholestasis * – No jaundice free period after physiological jaundice * – Associated congenital anomalies (malrotation of abdominal viscera, congenital heart disease) Perinatal type (80%) * – Normally developed biliary tree is destroyed following birth (virus induced injury to biliary epithelium) * – Late onset neonatal cholestasis (4-8 weeks) * – Jaundice free interval * – No associated congenital anomalies **Morphology** * Inflammation and fibrosing stricture of the hepatic and common bile ducts * Periductal inflammation of intrahepatic bile ducts – progressive destruction of intrahepatic biliary tree * Features of extrahepatic biliary obstruction * – Marked bile ductular proliferation * – Portal tract edema and fibrosis * – Parenchymal cholestasis ** **

Answer 2

**Etiology** * Excludes known associated factors * Alpha-1 antitrypsin * Extrahepatic biliary atresia * Infectious agents * 50-60% of cases of neonatal hepatitis * Male : Female – 2:1 **Microscopic morphology** * Giant cell transformation: diffuse, prominent * Ballooning * Acidophilic degeneration * cholestasis

Answer 3

**Morphological changes** * Multiple petechiae (80%) in Thymus, visceral/parietal pleura and epicardium. * Lungs: Congestion +/- pulmonary edema * Hypoplasia of arcuate nucleus in the brain stem. * Decrease in brain stem neuronal populations in some cases. Risk factors: Parental * Young maternal age (\<20) * Smoking during pregnancy * Drugs in either parent * Late / no prenatal care * Low socioeconomic group * African American or American Indian ethnicity * Risk factors: Infant * Brain stem abnormality associated with defective arousal / cardiorespiratory control * Prematurity +/or low birth weight * Male sex * Product of multiple birth * SIDS in an earlier sibling * Antecedent respiratory infections * Germline polymorphisms in autonomic nervous system genes **Morphology** * Multiple petechiae (80%) in Thymus, * visceral/parietal pleura and epicardium. * Lungs: Congestion +/- pulmonary edema * Hypoplasia of arcuate nucleus of **medulla** * Decrease in brain stem neuronal populations in some cases.

Answer 4

Rule out the following before DDx as SIDS: * Long QT syndrome (SCNSA + KCNQ1 mutations) (Na+ or K+ channel abnormalities.) * Fatty acid oxidation disorders (MCAD, LCHAD, SCHAD mutations) 5% * Histiocytoid cardiomyopathy (MTCYβ mutations) * Abnormal inflammatory responsiveness (Partial deletion of C4a and C4b)

Answer 5

Hematogenous spread/Transplacental infection: * TORCH: Tox, Other, Rubella, CMV, HIV & Herpes * SLAVE: Syphilis, L. monocytogenes, Adenovirus, Varicella, Enterovirus * Parvovirus B19 Ascending infection via cervix: mostly bacterial and some viral resulting in * Chorioamnionitis * Funisitis * Pneumonia * Sepsis * Meningitis * Note: L. monocytogenes causes necrotizing amnionitis in late gestation Sx: SGA infants.

Answer 6

Ocular lesions: * Cataracts. * Corneal changes * Microphthalmia. Cardiac lesions: * Patent ductus arteriosus. * Septal defects.

Answer 7

* CFTR encoded on chr 7q31.2 * Normal: PKA phosphorylates CFTR in apical membranes of eccrine glands. **Pathogenesis** With the absence of CFTR: * In the sweat gland: increased chloride and sodium concentration in sweat. * In the airway: * – Stimulated chloride secretion to the gland lumen does not occur. * – Increased sodium and water reabsorption leads to dehydration of the mucous layer. Types of mutations * 3 base pair deletion @ F508 (70%) * remaining patients exhibit multiple (more than 800) different mutations. **Morphology** Lung * Plugging of submucosal tracheobronchial mucous glands and ducts. * Obstruction of bronchioles with mucus, associated with marked hyperplasia and hypertrophy of the mucus-secreting cells. * As a consequence of bronchiolar plugging, there is: * – Atelectasis. * – **Emphysema** due to destruction of parenchyma. * Infections result in: * – Chronic bronchitis. * – Bronchiectasis -\> brochopneumonia * – Lung abscesses Pancreas * same mucous obstruction of ducts accompanied by: * – Secondary dilatation and cystic changes of the distal ducts and atrophy of secretory cells. * – Fibrosis * – Destruction of parenchyma * These effects result in chronic pancreatitis in 85% of patients with CF. Other organs * Liver - Focal biliary cirrhosis due to obstruction and bile duct hyperplasia. * Azoospermia and infertility in approximately 95% of males due to obstruction of the vas deferens and epididymis – atrophy & fibrosis * Meconium ileus in 15% of infants due to impaction of meconium in the terminal ileum with subsequent risk of perforation and peritonitis. **Sx** * Discovered between age of 2-12 months. * chronic pulm infections * Child presents with symptoms of malabsorption secondary to pancreatic insufficiency: * – Foul-smelling steatorrhea. * – Malnutrition * Edema * Hypoalbuminemia * – Failure to thrive Two clinical clues in children * **Nasal polyps** * **Rectal prolapse **

Answer 8

* AR Point mutation on 12q of Phenylalanine Hydroxylase (PAH) gene results in * – Hyperphenylalaninemia * – Formation of Phenylketones * Hyperphenylalaninemia causes irreversible brain damage * – Complete interference with amino acid transport system in brain * – Inhibiting the synthesis of neurotransmitters **Sx: **Mousy odour, fair skin, blond hair and blue eyes.

Answer 9

* AR deficiency of Galactose -1-phosphate uridyl transferase, the enzyme that catalyzes the conversion of galactose to glucose. * As a result galactose accumulates in the liver and other organs. **Sx:** * Infants fed milk rapidly develop hepatosplenomegaly, jaundice and hypoglycemia. * Cataracts and Mental retardation * Cirrhosis may develop in just a few months. * Galactose-free diet reverses many of the morphologic changes. **Gross Morphology**: extensive and uniform fat accumulation in liver and marked bile ductal proliferation, cholestasis and fibrosis.

Answer 10

* AR mutation characterized by chronic or intermittent jaundice and accompanied by a "black‟ liver. * Defective transport of conjugated bilirubin from hepatocytes to canalicular lumen * Associated defect in hepatic excretion of coproporyphrins **Microscopic**: accumulation of coarse, iron free, dark brown granules in hepatocytes and Kupffer cells, aligning in shape of canaliculi. **EM:** pigment is located in lysosomes and it appears to be composed of polymers of epinephrine metabolites, not bilirubin pigment **Sx:** * Most patients are asymptomatic except for mild intermittent jaundice. * Serum bilirubin levels – 2-5 mg/dl

Answer 11

* Familial conjugated Hyperbilirubinemia * Etiology unknown. * defect in the excretion of conjugated bilirubin into the biliary canaliculi with the bilirubin being absorbed into the blood. **Sx: **Characterized by jaundice, attacks of intermittent epigastric discomfort and occasionally abdominal pain, and fever. **Microscpic: **low-grade pigment deposition, dissociation of liver cells, occasional necrotic foci, and fibrin precipitation.

Answer 12

\>200 genetic syndromes are associated with an increased susceptibility to cancer. – Down syndrome (Trisomy 21) - Acute leukemia. – Deletion 13q - Retinoblastoma. – Wiskott Aldrich syndrome - Lymphoma. – Agammaglobulinemia - Acute lymphoblastic leukemia (= ALL).

Answer 13

* A name applied to many of the solid tumors of childhood because of their appearance. * This appearance reflects the “embryonal” origin of many of these tumors. **Microscopic: ** * Relatively homogeneous, densely "Small, Round, Blue Cells" * Despite histologic similarities, therapyand prognosis differ among these malignant neoplasms. * Clinicalinformation * Immunohistochemistry * Cytogenetics * Molecular genetics **Common types:** * Lymphoma/Leukemia * Medulloblastoma(CNSneoplasm) * Neuroblastoma * Rhabdomyosarcoma (Sarcoma) * Embryonal * Alveolar * Wilms tumor * Bone tumors * – Ewings sarcoma/PNET & t(11q22) * – Small cell osteosarcoma

Answer 14

* A poorly differentiated tumor arising from primitive neural crest cells that normally give rise to the adrenal medulla and sympathetic ganglia. * 7-10% of all childhood malignancies. * Second most common solid malignant tumor in children. * Most occur before 5 years of age. **Etiopath:** Germline mutation in ALK gene – familial predisposition to neuroblastoma. **Sx:** * \< 2 years - Mass in abdomen, mediastinum, or other sites, **fever, weight loss (systemic sx which other tumours may not induce)** * Older children – Signs of metastatic disease – bone pain, respiratory or gastrointestinal symptoms. * Blueberry muffin baby – disseminated neuroblastoma – multiple cutaneous metastasis with deep blue discoloration of the skin **Gross** * 40 % arise in adrenal medulla. * Remainder arise anywhere along the sympathetic chain * – paravertebral region of the abdomen (25%) * – posterior mediastinum (15%). . * Size varies from minute nodules to tumors weighing \>1 kg in weight * With increasing size, areas of: – Necrosis. * – Hemorrhage. * – Cyst formation. * Gross calcification in 40-50% **Microscopic** * Small, round, blue cell tumor with sheets of small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders * Neuropil - a faintly eosinophilic fibrillary material that corresponds to neuritic processes of the primitive neuroblasts. * Homer-Wright Pseudo rosettes - the tumor cells are concentrically arranged about a central space filled with neuropil. No lumen. * Neurosecretory granules on electron microscopy. * + for **neuron-specific** **enolase** and **synaptophysin** on immunohistochemistry. **Dx** * Elevated blood levels of catecholamines * Elevated urine levels of catecholamine metabolites * X –ray abdomen – **calcification in tumor** can be picked up **C&C** Characteristically, these tumors metastasize early with spread to: * Bone * Lymph nodes * Liver * Bone marrow * Subcutaneous tissue Prognostic factors * Younger -\> better prognosis * Poor prognosis mutations * Deletion distal 1p and gain of distal 17q * N-myc amplification – extrachromosomal double minute chromatin bodies or homogenously staining regions (HSR) on other chromosomes * Telomerase overexpression * Good prognosis: Tyrosine kinase receptor A (Trk-A) – increased expression

Answer 15

* Most common 1o renal tumour of childhood; aka nephroblastoma * Majority of cases are sporadic * 10% cases associated/risk factor with: * WAGR syndrome – deletion of WT1 gene * Denys-Drash syndrome –dominant, negative inactivating mutation of WT1 gene * Beckwith-Wiedemann syndrome – mutation of putative WT2 gene – overexpression of IGF2 protein * Mutations of β-catenin gene (10% of sporadic WT)

Answer 16

Genomic imprinting disorder on putative WT-2 gene * Macroglossia * Omphalocele * Gigantism **unilateral** * Adrenal cortical cytomegaly * Visceromegaly * Islet cell hypertrophy * Renal medullary dysplasia -\> immature renal cells and cartilage in kidney

Answer 17

* Gonadal dysgenesis * Renal abnormalities * WT-1 gene mutation (11p13) * 90% chance of Wilms tumor

Answer 18

Seen in the renal parenchyma adjacent to approximately 40% of unilateral tumors and nearly 100% of bilateral tumors. **Gross ** * Majority are large, Solitary, well circumscribed masses * 10% bilateral and multicentric **Microscopic** * Triphasic pattern: Embryonal tumor – recapitulates the normal development of the kidney. * Immature cells: glomeruli, tubules, etc... * Blastema – sheets of small round blue cells * Stroma – fibrocytic or myxoid in nature. **May have striated muscle.** * Epithelium - abortive tubules and glomeruli **Anaplastic Subtype (5% of WT) ** Characterized by: * Cells with hyperchromatic nuclei, \>3 times larger than those in adjacent cells of similar type. * Enlarged, bizarre, multipolar mitoses. Correlates with acquired TP53 mutations **Sx** * Abdominal pain (often detected when mom gives child a bath). * Hematuria. * Hypertension. * Acute abdominal crisis secondary to traumatic rupture -\> severe hemorrhage

Answer 19

* White pupil (= leukocoria). * Squint (= strabismus). * Poor vision. * Spontaneous hyphema (= hemorrhage into the anterior portion of the eye). * Red, painful eye. **Increased risk of:** * Osteogenic sarcoma * Ewing sarcoma/PNET * Pinealoblastoma **C&C: **Frequent complication is secondary glaucoma due to blockage of canal of Schlemm

Answer 20

* ≤ 4 months - ALL benign * At 1year 50% malignant * At 5years 100% malignant

Answer 21

Stage 1 – localized tumor with complete gross excision, Lymph nodes negative Stage 2A - localized tumor with **incomplete gross excision**, ipsilateral, non-adherent **Lymph nodes negative** Stage 2B – localized tumor with with or without complete gross excision, ipsilateral **non-adherent Lymph nodes positive** Stage 3 - Unresectable unilateral tumor infiltrating across the **midline** with or without regional lymph node involvement, or localized unilateral tumor with contralateral regional lymph node involvement Stage 4 – **metastatic** disease to the viscera, bone and/or distant lymph nodes Stage 4S (S=Special) – **Good prognosis** Localized primary tumor (stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow (\<10% of nucleated marrow cells are constituted by neoplastic cells)