Pediatric Tumors - Robbins & Kumar Basic Pathology

Overview

Tumorlike Lesions (Not True Neoplasms)

• Microscopically normal cells or tissues present in abnormal locations
• Examples: ectopic pancreatic tissue in the stomach wall, adrenal cells in the kidney, lungs, or ovaries
• Usually of little clinical significance but can be confused with neoplasms

• Excessive but focal overgrowth of cells and tissues native to the organ in which it occurs
• Mature cellular elements are identical to the normal organ but lack normal architecture
• The line between hamartoma and benign neoplasm is often unclear - both can be clonal
• Examples: hemangiomas, lymphangiomas, rhabdomyomas of the heart, adenomas of the liver
• Though histologically benign, can cause serious complications due to size or location

Benign Neoplasms

1. Hemangioma

• The most common neoplasm of infancy
• Both cavernous and capillary types occur; the latter are often more cellular than those in adults and may appear deceptively worrisome
• Predominantly in the skin - particularly face and scalp - as irregular, erythematous to violaceous lesions ranging from flat to plaque to nodular forms

FIG. 4.35 - Cutaneous hemangioma in infancy

• Hemangiomas may enlarge during the first few years of life but most spontaneously regress by age 5-8 years
• If needed, treatment includes laser therapy, beta-blockers, or surgery

2. Lymphangioma

• Benign proliferations of lymphatic channels
• Can occur superficially in the skin or in deeper locations (mouth, neck, axilla, mediastinum, retroperitoneum)
• Deep lesions may cause serious clinical complications due to their location

3. Teratoma

• Arise from totipotent cells and contain elements of all three germ layers
• Most common site: sacrococcygeal region (Fig. 4.37 below); also gonads, retroperitoneum, mediastinum
• The most common tumors of infancy in the first few months of life

FIG. 4.37 - Sacrococcygeal teratoma. Note the size of the lesion compared with that of the infant.

• Sacrococcygeal teratomas: ~75% are mature (benign); malignant teratomas are more common in male infants
• Malignant potential depends on age: those presenting in infancy tend to be benign; those presenting later are more likely malignant
• Associated with elevated alpha-fetoprotein (AFP) if malignant elements are present

Malignant Neoplasms

Key Differences from Adult Cancers

"Small, Round, Blue Cell Tumors" of Childhood

• Neuroblastoma
• Lymphoma
• Rhabdomyosarcoma
• Ewing sarcoma
• Medulloblastoma
• Retinoblastoma
• Some cases of Wilms tumor

The Three Classic Pediatric Malignancies

1. Neuroblastoma

• Median age at diagnosis: ~2 years; 90% diagnosed before age 5
• Most cases are sporadic; ~1-2% are familial (ALK mutations, germline)

• Adrenal medulla (~40%)
• Paraspinal sympathetic ganglia (abdomen, posterior mediastinum, pelvis, neck)

• MYCN amplification - present in ~25% of cases; strongly associated with poor prognosis
• 1p deletion (loss of tumor suppressor locus)
• 17q gain
• ALK mutations (familial cases)

• Sheets of small, round, blue cells with dark nuclei and scant cytoplasm
• Homer-Wright pseudorosettes: tumor cells arranged around a central neuropil
• Variable degrees of neuroblastic differentiation

• Abdominal mass (most common presentation) that may cross the midline
• Hypertension (from catecholamine secretion)
• Elevated urinary catecholamines: VMA (vanillylmandelic acid) and HVA (homovanillic acid) - used for diagnosis and monitoring
• "Blueberry muffin" appearance - subcutaneous metastatic nodules in neonates
• Periorbital ecchymosis ("raccoon eyes") from orbital metastases
• Paraneoplastic syndrome: opsoclonus-myoclonus ("dancing eyes, dancing feet")
• Stage 4S disease (special stage in infants <1 year): liver, skin, and bone marrow involvement but WITHOUT bone metastases - can spontaneously regress

• Age and stage are the strongest prognostic factors
• Infants (<18 months): favorable prognosis even with metastatic disease (especially 4S)
• Older children: poor prognosis with metastatic disease
• MYCN amplification = poor prognosis regardless of stage
• Trk-A (high neurotrophin receptor expression) = favorable prognosis
• 5-year survival: ~50% overall; >90% in low-risk, ~20% in high-risk

2. Wilms Tumor (Nephroblastoma)

• Peak age: 3-4 years
• Bilateral in ~5-10% of cases
• Associated syndromes:
  • WAGR syndrome - Wilms tumor, Aniridia, Genitourinary anomalies, intellectual disability (mental Retardation); deletion of WT1 gene (chromosome 11p13)
  • Denys-Drash syndrome - Wilms tumor, gonadal dysgenesis, nephropathy; point mutation in WT1
  • Beckwith-Wiedemann syndrome - organomegaly, macroglossia, hemihypertrophy, Wilms tumor; associated with WT2 locus (11p15.5) or IGF2 overexpression
  • WTX gene mutations (on X chromosome) - present in ~30% of sporadic cases

• Classic triphasic pattern:
  1. Blastemal component - sheets of small, undifferentiated cells (worst prognosis)
  2. Stromal component - spindle-shaped cells
  3. Epithelial component - primitive tubules/glomeruli
• Gross: large, solitary, encapsulated mass that distorts the kidney; gray-tan cut surface with areas of hemorrhage, cyst, necrosis
• Anaplasia (nuclear enlargement with multipolar mitotic figures) is the most important adverse histologic feature

• Large abdominal/flank mass, usually unilateral and detected incidentally by parents or doctor
• Hematuria, hypertension, abdominal pain
• The mass rarely crosses the midline (contrast with neuroblastoma)

• WT1 tumor suppressor gene (11p13) - involved in genitourinary development
• WT2 (11p15.5) - associated with Beckwith-Wiedemann syndrome
• WTX gene mutation (~30% sporadic cases)
• Mutations in CTNNB1 (β-catenin gene) in ~15% of cases

• Excellent overall - one of the great success stories of oncology
• 5-year survival: >90% with combined surgery + chemotherapy +/- radiotherapy
• Anaplastic histology confers worse prognosis
• Stage remains the most important prognostic factor

3. Retinoblastoma

• Most common intraocular tumor of children
• Arises from immature retinal cells (retinoblasts)
• The classic example of the "two-hit hypothesis" of tumor suppressor gene inactivation (RB1 gene, chromosome 13q14)
  • Hereditary form: one germline mutation + one somatic mutation; often bilateral and multifocal; autosomal dominant inheritance pattern
  • Sporadic form: two somatic mutations; usually unilateral, unifocal
• Clinical: leukocoria ("cat's eye reflex" - white pupillary reflex), strabismus, visual loss
• Morphology: small, round blue cells with Flexner-Wintersteiner rosettes and fleurettes
• Spontaneous regression via calcification can occur (leading to "retinocytoma")
• Treatment: chemotherapy, laser photocoagulation, cryotherapy, radiation, enucleation in advanced cases
• Germline RB1 carriers have markedly increased risk of secondary malignancies (osteosarcoma, soft tissue sarcomas) - "second-hit" in other tissues

Summary Table