Pediatric Neoplasia

PEDIATRIC NEOPLASIA Philip R. Faught, M.D.

MALIGNANT PEDIATRIC TUMORS • The leading natural cause of death under age 14 (accidents are #1) • Brain tumors and leukemia/lymphoma account for about two-thirds • Pediatric and adult cancers are different

Soft-Tissue Sarcoma 7%

Other 8% Leukemia 30%

Bone 5% Liver 1% Kidney 6% Retinoblastom 3% Neuroblastoma 8%

Lymphoma 13% CNS 19%

Table 10-6. Common Malignant Neoplasms of Infancy and Childhood 0-4 Years Leukemia Retinoblastoma Wilms Tumor Hepatoblastoma Soft tissue sarcoma (especially rhabdomyosarcoma) Teratomas CNS tumors Neuroblastoma

5 to 9 Years

10 to 14 Years

Leukemia Retinoblastoma Hepatoblastoma Hepatoblastoma Soft tissue sarcoma Soft tissue sarcoma

CNS tumors Ewing’s tumor Lymphoma

Osteogenic sarcoma Thyroid carcinoma Hodgkin’s disease

DIFFERENCES IN PEDIATRIC CANCER 1. Site of origin different 2. Type – sarcomas, “blastomas,” small round blue cell tumors 3. Bulk typically greater but no cachexia 4. Prognosis often better 5. Neonatal tumors – tend to be less aggressive 6. Usually no precursor lesions in ped cancer (exception – some Wilms tumors)

Congenital Sacrococcygeal Teratoma – 1415 g Tumor

Preterm female with large sacrococcygeal teratoma, died at 7 days of age due to high output cardiac failure

Congenital Cervical Teratoma – One day Old Female

Newborn with maxillofacial teratoma; survival was about 15 minutes

BLASTOMA – A neoplasm composed of embryonic cells derived from the blastema of an organ or tissue [Gr. BLASTOS = germ]

BLASTEMA – A primitive group of cells that give rise to an organ or part in development or regeneration.

The Important Blastomas Nephroblastoma (Wilms Tumor) – Kidney Neuroblastoma – adrenal medulla and sympathetic nervous system Hepatoblastoma – liver Pleuropulmonary blastoma – lung/pleura Pancreatoblastoma – pancreas Retinoblastoma – neural retina Medulloblastoma - cerebellum

Small Round Blue Cell Tumors • So-called because they consist of primitive blastema-like cells • Some adult tumors also have this appearance (oat cell carcinoma of lung) • Important to classify since treatment varies widely

Important Pediatric Cancers Not Named as Blastomas Primitive neuroectodermal tumor (PNET) – Central (medulloblastoma) – Peripheral (bone and soft tissue)

Rhabdomyosarcoma Ewing’s Sarcoma Lymphoma/leukemic infiltrates Osteogenic Sarcoma Other soft tissue sarcomas

Neuroblastoma • The most common malignant solid tumor of childhood (after CNS) • Most patients <5 years old, half <2 years old, may be congenital • Arise in the adrenal medulla, but also along the sympathetic chain ganglia (or dorsal root ganglia) anywhere from the base of the skull to the pelvis

Neuroblastoma • Usually sporadic, seen with increased incidence in VRD, tuberous sclerosis, Hirschsprung’s disease, others • May present with mass only or constitutional symptoms • Commonly metastatic at presentation – may involve bizarre sites (orbits, skin) • 90% secrete catecholamines but HTN rare

Clinical Manifestations of Neuroblastoma

Large abdominal mass

Horner’s syndrome on the left

Multiple bluish subcutaneous Metastases (blueberry muffin)

Metastases to periorbital bones of both eyes

Neuroblastoma Stage IV S (Special) • Metastases limited to liver, skin, bone marrow • Patients usually <1 year old and with small primaries • Have an unusually good prognosis compared with stage IV

Neuroblast Cells From Neural Crest

Adrenal Medulla And Paraganglia

Peripheral N.S. Neurons (ganglion cells)

Nerve Sheath Cells (Schwann cells)

PRIMITIVE NEUROBLASTOMA RECOGNIZABLE NEUROBLASTOMA DIFFERENTIATING NEUROBLATOMA GANGLIONEUROBLASTOMA GANGLIONEUROMA (Benign)

Common Chromosomal Abnormalities in Neuroblastoma

Differentiating Neuroblastoma, Posterior Mediastinal, 3 year old

Ganglioneuroma, Posterior Mediastinal,

Neuroblastoma – Poorly Differentiated Area

Neuroblastoma – Area with Septation and Neuropil

Neuroblastoma – Homer-Wright Rosettes

Neuroblastoma Electron Microscopy

Neuroblastoma Electron Microscopy

Differentiating Neuroblastoma

Differentiating Neuroblastoma, >5% ganglion cells but still with Immature neuroblasts

Ganglioneuroma – mature ganglion Cells within a schwannian stroma, no immature neuroblasts

NEUROBLATOMA PROGNOSTIC FACTORS 1.

Age and histology (Shimada scheme)

2.

Stage

3.

Location – abdominal worse than mediastinum, neck pelvis; adrenal primary worse than other sites (except IV S)

4.

N-myc oncogene – aggressive tumors show amplification

5.

Many others – see handout and Robbins text

Wilms Tumor (Nephroblastoma) • Most common malignant kidney tumor in children • About 500 new cases per year in U.S. • Peak age 2-4 years, rarely congenital • Most are sporadic but also occurs in hereditary forms

Conditions Associated with Wilms Tumor • Aniridia (up to 33% will develop Wilms tumor) – see discussion of WT1 and WT2 genes in Robbins text • WAGR syndrome (Wilms tumor , aniridia, GU anom., retardation) • Drash syndrome (Wilms tumor, pseudohermaphroditism, nephrotic synd) • Beckwith-Weidemann syndrome (Exomphalos, macroglossia, gigantism) and Perlman’s syndrome (Wilms tumor, renal dysplasia, fetal gigantism, pancreatic endocrine hyperplasia, MCA, MR)

Conditions Associated with Wilms Tumor •

Hemihypertrophy

•

GU anomalies, skin hamartoma, hemangiomas, malformed ears

•

Increased incidence in VRD, Bloom’s syndrome, trisomy 13 & 18, intersex anomalies

Wilms Tumor Clinical Presentation • Typical history is abdominal mass noted by mother • Hematuria 5-10% • Sudden hemorrhage into Wilms tumor may cause anemia, HTN, rapidly increasing abdominal mass (Ramsey’s Triad) • Metastases to nodes, liver, lungs; bone metastases extremely rare

Neglected Wilms tumor in a young girl. The child had marked hypertension

Wilms tumor 757 g 22 month old female

Wilms Tumor with Invasion Of the Renal Pelvis, 900 g, 13 Month Old Female

Wilms Tumor with Hemorrhage 3 Year Old Female

Wilms Tumor Microscopic from Robbins 4th Edition

Wilms Tumor – Triphasic Pattern

Wilms Tumor – Blastema and Stroma

Wilms Tumor – Blastema and Epithelium

Wilms Tumor – with Fetal Skeletal Muscle

Anaplasia in a Wilms’ tumor with a bizarre mitotic figure

Unfavorable Histology in Wilms’ Tumors • About 5% of WT are unfavorable histology • Characterized histologically by increased nuclear anaplasia/hyperchromasia and by bizarre mitotic figures • UH tumors are more resistant to chemoTx, and have a worse prognosis if beyond stage 1 • Anaplasia correlates with p53 mutations

Wilms Tumor Prognosis • Survival of low stage favorable histology >90% • Prognosis not as strikingly related to age as with neuroblastoma • Worse prognosis with extensive lung metastases or with UH beyond stage 1