Nodular Ganglioneuroblastoma [nodules of neuroblastic component (Schwannian stroma poor) + Schwannian stroma rich component of ganglioneuroma, maturing and mature]
- Single nodule of cellular tumor along with adjacent diffuse architecture and areas of hemorrhage
- Abrupt transition between sheets of ganglion cells and nodule of neuroblasts, in an abundant neuropil background
- Nodular areas of neuroblastic cells with pale pink fibrillar material of neuritic cell processes, appears in a Schwannian stroma poor/absent background.
- Neuroblastic cells are poorly differentiated type with low MKI (mitosis‐karyorrhexis index): round ovoid and irregular nuclear border with salt and pepper chromatin and vary scanty cytoplasm. Few cells show pleomorphic and hyperchromatic nuclei also.
- Scattered neuroblastic cells are multinucleated and horseshoe shape in appearance, representing early immature ganglion cells/differentiation with low MKI (mitosis‐karyorrhexis index).
- Nucleoli is not seen. It is common in undifferentiated neuroblastic cells.
- Calcification and Homer Wright pseudo rosettes are not apparent. Homer Wright pseudo rosettes suggest differentiated neuroblastic component.
- Ganglion cells look as a large and some pleomorphic cells, with eccentric nuclei, prominent nucleoli and abundant eosinophilic cytoplasm in a Schwannian spindle stroma rich background as well as in a fibrillar background (stroma poor).
- Many foci of Nissl substance are seen as pink granular rounded structure.
- Areas of localized soft tissue infiltration is seen
- Some of foci of lymphocytic aggregates, also around blood vessels are seen.
Points of pathoclinics:
- Here the ganglioneuromatous component is >50% of total tumor volume. Grossly evident multiple nodular pattern along with sharp and abrupt demarcation of haemorrhagic nodular neuroblastic component from ganglioneuromatous component in a rich schwannian stroma favors Nodular ganglioneuroblastoma.
- Differentiating neuroblastoma comprising of <50% of ganglioneuromatous component and poorly defined transition between neuroblastic and ganglionic component.
- First step in the evaluation and reporting is to look for the amount of ganglioneuromatous component and schwannian stroma (stroma dominant = Ganglioneuroma, maturing or mature; stroma rich =Ganglioneuroblastoma intermixed; stroma poor = Neuroblastoma)
- Next, in schwannian stroma poor tumors (Neuroblastoma), look for age, differentiation and MKI (mitosis‐karyorrhexis index) for prognostic evaluation. Age <1.5 years, Low MKI (<100 and <200 also) and >5% differentiating elements has favourable prognosis. Age >5 years, even with low MKI or high MKI and undifferentiated component has poor survival.
- Second step is to evaluate the nodular pattern: Schwannian stroma rich tumor with absence of nodular pattern has good prognosis, in contrast any nodular pattern macroscopically is Nodular Ganglioneuroblastoma, and has poor survival. Genetically neuroblasts and ganglion cells of nodular ganglioneuroblastoma are related and may arise from the same clone but the Schwann cells have a different origin and may be derived from a non-neoplastic neural crest precursor.
- Composite Ganglioneuroblastomas has three prognostic subgroups on the basis of pattern of neuroblastic foci: Type A Intermixed: individual microscopic nests of neuroblasts (excellent survival); Type B Intermixed: microscopic aggregates of multiple neuroblastic nests (Good survival); and Nodular: macroscopic visible nodules of neuroblastic componet (Poor survival)
- Calcification should be evaluated but currently not considered as a any prognostic indicator.
- Any surgical margin positivity should be mentioned in the pathology report.
- Common age of presentation is less than 4 years, with abdominal (around adrenal and retroperitoneal location) or non-abdominal mass (thorax and neck; less common site of involvement), watery diarrhoea, headache along with increased urinary excretion of homovanillic acid (HVA), vanillylmandelic acid (VMA)and dopamin level are important features in arriving the diagnosis.
- Advanced stage and metastasis is common at the presentation.
- Poor prognostic factors are: age >5 years, high MKI (>200), undifferentiated areas (less than 5% differentiating/gangliocyte cells), and nodular component.
- S 100 and Galectin-3 positivity in schwannian stroma is a good prognostic factor.
- MYCN status (n-myc) amplification, chromosome 1p deletions, chromosome 17q amplification, diploid DNA and VMA-to-HVA ratio of less than 1 suggest an unfavorable prognosis.
- High serum levels of neuron-specific enolase, ferritin, lactate dehydrogenase, chromogranin A, creatine kinase BB are associated with poor prognosis.
- Pathology report should mention the limitation of evaluation of prognostic parameter based on limited biopsy sample.
- MYO5A-NTRK3 fusion is seen in central nervous system ganglioneuroblastoma (WHO grade IV embryonal tumors, considering the aggressive behavior). Take note that MYO5A-NTRK3 fusion is common with melanocytic tumors.
- Newborn ganglioneuroblastoma is very uncommon.
- ALK mutational analysis in blood is helpful to identify patients with ALK mutation in neuroblastoma. These are candidates for crizotinib or other ALK‐targeting molecules when no tumor tissue is available.
Angelini, P., Baruchel, S., Marrano, P. et al. The neuroblastoma and ganglion components of nodular ganglioneuroblastoma are genetically similar: evidence against separate clonal origins. Mod Pathol 28, 166–176 (2015). https://doi.org/10.1038/modpathol.2014.90
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