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121

Rotor syndrome path

low-grade pigment deposition, dissociation of liver cells, occasional necrotic foci, and fibrin precipitation.

122

Common Malignant Neoplasms of Infancy and Childhood

123

Special Predisposing Factors child cancers 

Chromosomal and genetic syndromes.

• Congenital immunodeficiency syndromes.

• >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).

124

Common “Small, Round, Blue Cell” Tumors of Childhood

• Lymphoma/Leukemia

• Medulloblastoma(CNSneoplasm)

• Neuroblastoma

• Rhabdomyosarcoma (Sarcoma) – Embryonal

– Alveolar

• Wilmstumor

• Bonetumors

– Ewing‟s sarcoma/PNET – Small cell osteosarcoma

125

Neuroblastoma general characterisitcs 

poorly differentiated tumor arising from primitive neural crest cells

  • normally give rise to the adrenal medulla and sympathetic ganglia.

  • Second most common solid malignant tumor in children.

  • Before age of 5

  • Germline mutation in ALK gene – familial predisposition to neuroblastoma.

126

Neuroblastoma clinical features

• < 2 years - Mass in abdomen, mediastinum, or other sites, fever, weight loss

• 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

127

Neuroblastoma gross pathology

• 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%.

128

 Homer-Wright Pseudo rosette

the tumor cells are concentrically arranged about a central space filled with neuropil. No lumen.

 

Found in neuroblastomas

129

Neuroblastoma Microscopy

Small, round, blue cell tumor with sheets of small, primitive-appearing cells with dark nuclei, scant cytoplasm, and poorly defined cell borders

130

Neuropil 

a faintly eosinophilic fibrillary material that corresponds to neuritic processes of the primitive neuroblasts.

 

131

Neuroblastoma spreads to

• Bone.

• Lymph nodes.

• Liver.

• Bone marrow.

• Subcutaneous tissue.

132

Neuroblastoma dx

• Elevated blood levels of catecholamines

• Elevated urine levels of catecholamine metabolites

– Vanillylmandelic acid (VMA)

– Homovanillic acid (HVA)

• X –ray abdomen – calcification in tumor can be picked up

133

Neuroblastoma Prognostic factors

• Age of the patient

– < 1 year excellent prognosis – 1-5 years – intermediate

– > 5 years – poor prognosis

• Deletion distal 1p and gain of distal 17q - poor prognosis

• N-myc amplification – extrachromosomal double minute chromatin bodies or homogenously staining regions (HSR) on other chromosomes – poor prognosis

• Telomerase overexpression - poor prognosis

• Tyrosine kinase receptor A (Trk-A) – increased expression indicates good prognosis

134

Nephroblastoma (Wilms Tumor)

malignant embryonal neoplasm derived from nephrogenic blastemal cells

• Most common primary renal tumor of childhood

• Peak incidence – 2-5 years of age

135

Wilms patho

• 10% cases associated 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)

136

Beckwith-Wiedemann Syndrome

• Macroglossia

• Omphalocele

• Gigantism

• Adrenal cortical cytomegaly

• Visceromegaly

• Islet cell hypertrophy

• Renal medullary dysplasia

137

Denys-Drash Syndrome

• Gonadal dysgenesis

• Renal abnormalities

• WT-1 gene mutation

• 90% chance of Wilms‟ tumor

138

ANIRIDIA (WAGR S.)

 

• Aniridia

• Genitalabnormalities • Mentalretardation

• WT-1(11p13)

• 33%ChanceofWilms

139

Nephrogenic rests- precursor lesion

Seenintherenal parenchyma adjacent to approximately 40% of unilateral tumors and nearly 100% of bilateral tumors

140

Wilms microscopy

Triphasic pattern: Embryonal tumor – recapitulates the normal development of the kidney.

• Blastema – sheets of small round blue cells

• Stroma – fibrocytic or myxoid in nature. May have striated muscle.

• Epithelium - abortive tubules and glomeruli

141

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

142

Anaplastic Subtype 

Clinical presentations

• Usually comes to clinical attention due to the detection of an abdominal mass by a parent when bathing or clothing a child.

• Other common presentations:

– Abdominal pain.

– Hematuria.

– Hypertension.

– Acute abdominal crisis secondary to traumatic rupture.

143

Wilms spread

• “3L‟s”:

– Regional lymph nodes.

– Lungs.

– Liver.

• Metastatic sites other than these three sites are unusual and should suggest other diagnoses

144

Most common intraocular malignant neoplasm of childhood.

Retinoblastoma 

145

Retinoblastoma genetics 

• 40% congenital - RB1 gene - multiple tumors – bilateral

• 60% sporadic-unifocal, unilateral.

146

Age retinoblastoma 

Within first 2 years 

147

Retinoblastoma

Presentation

– White pupil (= leukocoria).

– Squint (= strabismus).

– Poor vision.

– Spontaneous hyphema (= hemorrhage into the anterior portion of the eye).

– Red, painful eye.

148

• Composed of small round cells with large hyperchromatic nuclei and scant cytoplasm.

• Flexner-Wintersteiner rosettes- Clusters of cuboidal tumor cells arranged around a central lumen

Microscopy 

REtinoblastoma 

149

Retinoblastoma course 

• Extension into optic nerve and/or subarachnoid space (CSF) with intracranial spread.

• Invasion of blood vessels, especially in the highly vascular choroid, with subsequent hematogeneous metastases.

• Frequent complication is secondary glaucoma

150

Retinoblastoma

Prognosis

• Always fatal if untreated.

• 90% survival with early diagnosis and modern therapy.