Neuroblastoma and Ganglioneuroblastoma



Neuroblastoma and Ganglioneuroblastoma


Jessica Comstock, MD

Cyril Fisher, MD, DSc, FRCPath





Key Facts


Terminology



  • Malignant tumor derived from primordial neural crest cells


Clinical Issues



  • 3rd most common malignant tumor in children


  • 90% diagnosed by age 5 years


  • Follows distribution of sympathetic ganglia, also adrenal medulla


  • Presentation depends on age of patient, location of tumor, and associated clinical syndromes


  • Urine catecholamines elevated in 95% of patients with neuroblastoma (NB)


Microscopic Pathology



  • International Neuroblastoma Pathology Committee


Classification



  • Undifferentiated NB


  • Poorly differentiated NB


  • Differentiating NB


  • Nodular GNB


  • Intermixed GNB


  • Mitotic-karyorrhectic index (MKI)


Ancillary Tests



  • N-myc amplification is associated with worse prognosis


Top Differential Diagnoses



  • Alveolar rhabdomyosarcoma (ARMS)


  • Ewing sarcoma/primitive neuroectodermal tumor (PNET)


  • Ganglioneuroma


  • Lymphoma






This low-power view of a poorly differentiated neuroblastoma shows thin septa of schwannian stroma image. Pale, eosinophilic neuropil image is seen in places between the nodules or nests of neuroblastoma cells.






A typical intermixed ganglioneuroblastoma is seen in this image. The tumor is composed of a mixture of maturing ganglion cells image, neuroblasts image, and abundant schwannian stroma image.


TERMINOLOGY


Abbreviations



  • Neuroblastoma (NB)


  • Ganglioneuroblastoma (GNB)


Synonyms



  • Schwannian stroma-poor neuroblastic tumor (neuroblastoma)


  • Schwannian stroma-rich neuroblastic tumor (ganglioneuroblastoma)


Definitions



  • Malignant tumor derived from primordial neural crest cells


  • On maturational spectrum of neuroblastic tumors


  • NB is least differentiated



    • GNB is moderately differentiated


    • Ganglioneuroma (GN) is well-differentiated, benign


ETIOLOGY/PATHOGENESIS


Developmental Anomaly



  • Derived from primordial neural crest cells



    • These cells migrate from spinal cord to adrenal medulla and sympathetic ganglia


CLINICAL ISSUES


Epidemiology



  • Incidence



    • About 1 in 10,000 children


    • 3rd most common malignant tumor in children



      • Most common extracranial solid tumor in children


    • Usually sporadic



      • Some autosomal dominant familial cases have been seen


    • Screening not recommended


  • Age



    • Half of patients diagnosed by age 2 years


    • 90% diagnosed by age 5 years


    • About 1/4 are congenital, with some detected prenatally on ultrasound


  • Gender



    • Slight male predominance


  • Ethnicity



    • Less common in African-Americans


Site



  • Follows distribution of sympathetic ganglia



    • Paramidline from base of skull to pelvis


    • Most common in abdomen and retroperitoneum


  • Adrenal medulla


  • Dorsal root ganglia


  • Metastases


  • Bone



    • Lymph nodes


  • Liver


  • Skin


Presentation



  • Depends on age of patient, location of tumor, and associated clinical syndromes


  • Most have nonspecific symptoms



    • Fever, weight loss, diarrhea, anemia, hypertension


  • Fetuses may have hydrops


  • Palpable mass in about half


  • About 2/3 have metastases on presentation


  • “Blueberry muffin” baby



    • Blue-red cutaneous masses in infants


  • Myoclonus-opsoclonus syndrome



    • Associated with good prognosis


    • Rapid, alternating eye movements and myoclonic movements of extremities


    • Resolves with tumor eradication


  • Other associated syndromes include



    • Myasthenia gravis


    • Beckwith-Wiedemann syndrome



    • Cushing syndrome


    • Neurofibromatosis


    • Fetal hydantoin syndrome


    • Hirschsprung disease


Laboratory Tests



  • Urine catecholamines (elevated in 95% of patients with NB)



    • Epinephrine


    • Norepinephrine


    • Homovanillic acid (HVA)


    • Vanillylmandelic acid (VMA)



      • VMA/HVA ratio > 1.5 is associated with better prognosis


  • Lactate dehydrogenase



    • > 1500 IU/L associated with worse clinical outcome


  • Ferritin



    • > 142 ng/mL associated with worse clinical outcome


  • Neuron-specific enolase (NSE)



    • > 100 ng/mL associated with worse clinical outcome


Natural History



  • 1-2% will spontaneously regress



    • Most in children under age 1 year


  • NB can metastasize widely via lymphatics and vessels


Treatment



  • Low risk



    • Surgery or observation alone


  • Intermediate risk



    • Surgery and adjuvant chemotherapy


  • High risk



    • Induction chemotherapy


    • Delayed tumor resection


    • Radiation of primary site


    • Myeloablative chemotherapy with stem cell recovery


Prognosis



  • Favorable prognostic factors



    • Age < 1.5 years at diagnosis


    • Favorable histology


    • Stage 1, 2, or 4S



      • Related to location of tumor


    • No N-myc amplification


    • Hyperdiploidy


    • No loss of 1p


    • High expression of TrKA


    • Normal serum ferritin, NSE, and LDH


    • Urinary VMA/HVA ratio > 1.5


IMAGE FINDINGS


General Features



  • Extensive radiographic evaluation is required to determine extent of disease and identify metastatic foci


  • Calcifications often seen in central portion of tumor


Bone Scan



  • Radiolabeled metaiodobenzylguanidine (MIBG) incorporates into catecholamine-secreting cells and can detect neuroblastoma


MACROSCOPIC FEATURES


General Features



  • Neuroblastoma



    • Fine membranous capsules


    • Cut surface is soft, fleshy, often with hemorrhage and necrosis


  • Ganglioneuroblastoma



    • Cut surface is firm, gray-white


    • Nodular GNB must have grossly visible, usually hemorrhagic nodules


    • Intermixed GNB can look like NB or GN depending on extent of differentiation


Size



  • Average: 6-8 cm diameter


MICROSCOPIC PATHOLOGY


Histologic Features



  • Neuroblasts




    • Small round blue cells


    • Very little cytoplasm


  • Homer-Wright pseudorosette



    • Neuroblasts forming a ring around central core of cytoplasmic processes


  • Ganglionic differentiation



    • Cells enlarge


    • Increased eosinophilic or amphophilic cytoplasm


    • Nuclear chromatin pattern becomes vesicular


    • Must have synchronous differentiation of cytoplasm and nucleus


  • Neuropil



    • Fibrillar eosinophilic matrix


  • Mitotic-karyorrhectic index (MKI)



    • Count of cells undergoing mitosis or karyorrhexis, per 5,000 cells



      • Can be estimated


    • Low: < 100 cells per 5,000


    • Intermediate: 100-200 cells per 5,000


    • High: > 200 cells per 5,000


International Neuroblastoma Pathology Committee (INPC) Classification



  • a.k.a. Shimada classification


  • Undifferentiated NB



    • No ganglionic differentiation


    • No neuropil


    • No or minimal schwannian stroma


    • Often requires immunohistochemistry for accurate diagnosis


  • Poorly differentiated NB



    • < 5% of tumor cells showing ganglionic differentiation


    • Neuropil background


    • No or minimal schwannian stroma


  • Differentiating NB



    • > 5% of tumor cells showing ganglionic differentiation


    • Usually more abundant neuropil


    • Usually more prominent schwannian stroma



      • Must be < 50%


  • Nodular GNB



    • Grossly identifiable nodules will be neuroblastoma


    • Abrupt demarcation between stroma-poor neuroblastoma and stroma-rich component


    • Fibrous pseudocapsule often seen surrounding NB component


    • > 50% schwannian stroma


  • Intermixed GNB



    • Microscopic nests of neuroblastoma within schwannian stroma


    • > 50% schwannian stroma


  • Do not classify post-treatment resections



    • “Neuroblastoma with treatment effect” is sufficient


  • May classify metastatic disease if resection/biopsy is pre-treatment


ANCILLARY TESTS


Immunohistochemistry



  • Neuron-specific enolase (NSE)



    • Most sensitive but least specific


    • Is found at least focally even in very undifferentiated NBs


  • NB84(+) in almost all NBs



    • Not specific; occasionally positive in other small round cell tumors


  • S100 protein



    • Positive in schwannian stroma


  • Other useful positive immunostains include



    • Chromogranin


    • Synaptophysin


    • Protein gene product 9.5 (PGP9.5)


    • CD56


Cytogenetics



  • MYCN



    • Amplification is associated with worse prognosis


    • Usually seen in advanced disease


  • DNA ploidy



    • Near-diploidy or tetraploidy is associated with worse prognosis


    • Hyperdiploidy is associated with better prognosis


  • Loss of heterozygosity of 1p and 11q



    • Both associated with worse prognosis


  • TrkA (high-affinity nerve growth factor receptor)



    • Increased expression associates with better prognosis


Electron Microscopy



  • Wide range of cytologic differentiation


  • Dense core of neurosecretory granules



    • Found in elongated cell processes


    • 100 nm in diameter


    • Dense core surrounded by clear halos and delicate outer membranes


DIFFERENTIAL DIAGNOSIS


Alveolar Rhabdomyosarcoma (ARMS)



  • Clinical presentations may be similar


  • More marked alveolar pattern except in solid variant


  • More pleomorphism


  • Cells have more abundant cytoplasm than NB


  • Diffuse immunoreactivity for desmin in cytoplasm


  • Myogenin(+) in nuclei


  • Characteristic t(1;13) or t(2;13) with PAX-FOXO1 fusions


Ewing Sarcoma/Primitive Neuroectodermal Tumor (PNET)



  • Usually in older patients


  • Cells have finely stippled chromatin and glycogen-filled cytoplasm


  • CD99 usually shows diffuse membranous immunoreactivity


  • Specific gene fusions, most commonly EWSR1-FLI1


Lymphoma



  • Lacks NSE, synaptophysin, and chromogranin


  • Has confirmatory lymphoid markers



    • CD45, CD3, CD20


    • TdT in lymphoblastic lymphoma



Maturing Ganglioneuroma



  • Differs from intermixed GNB in having single cells instead of nests of cells within schwannian stroma


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Jul 9, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Neuroblastoma and Ganglioneuroblastoma

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