**2. Imaging and histopathology**

#### **2.1 Imaging**

*Pheochromocytoma, Paraganglioma and Neuroblastoma*

**I** Neuroblastoma (Schwannoma stroma-poor)

**III** Ganglioneuroma (Schwannoma stroma-dominant)

**Type Description**

Stage 1 Complete gross excision of localised tumour,

Stage 2A Incomplete gross excision of localised

Stage 2B Complete or incomplete gross excision of localised tumour

Stage 3 a. Unresectable unilateral tumour infiltrating across the midline OR

b. Localised unilateral tumour

c. Unresectable midline tumour with

distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except 4S)

involvement of skin, liver, and/or less than

and International Neuroblastoma Staging System is illustrated in **Tables 1** and **2**, respectively. There are even reports of neuroblastoma occurring post-radiation in

Patients usually present with features of intracranial mass lesion and raised intracranial pressure. Secondary neuroblastoma is mainly extra-axial pathology. It presents as a bony lesion involving the calvaria and extradural mass lesion. However, the lesion can produce haemorrhagic deposits in the parenchyma and increase intracranial

10% of bone marrow cellularity (ONLY applies to children less than 1 year

OR

bilateral extension

Stage 4 Any primary tumour with involvement of

Stage 4S Any localised primary tumour with

of age)

*International neuroblastoma staging system.*

children and adults [19–22].

**1.7 Clinical features**

tumour

stroma-poor)

**V** NT, unclassifiable

**Table 1.**

with or without positive microscopic margins

*The international neuroblastoma pathology classification of neuroblastoma (Shimada system) [1].*

**II** Ganglioneuroblastoma, intermixed (Schwannoma stroma-rich)

**IV** Ganglioneuroblastoma, nodular (composite schwannoma stroma-rich/stroma-dominant and

Negative ipsilateral non-adherent lymph node(s) (lymph node(s) attached to and removed with the primary tumour may be

Negative ipsilateral non-adherent lymph node(s) (lymph node(s) attached to and removed with the primary tumour may be

Positive ipsilateral non-adherent lymph node(s); contralateral lymph node(s)

a. Positive or negative regional lymph

b. Contralateral positive regional lymph

c. May be "unresectable" due to positive

bilateral lymph node(s)

positive)

positive)

negative for tumour

node(s) OR

node(s) OR

**66**

*Source: [9].*

**Table 2.**

A typical CT picture of PCNS-NB shows a large intra-axial lesion with calcifications, cystic degeneration and areas of haemorrhage [24]. Perilesional oedema may be limited as compared to the size of the lesion [24]. On post-contrast CT images, uniform enhancement is seen in solid masses, and heterogeneous contrast enhancement is seen in lesions with cystic degeneration and extensive calcifications. Additionally, intraventricular lesions can demonstrate subependymal masses and help in differentiating these lesion from other differential diagnoses of intraventricular mass lesions. MR imaging of these tumours shows inhomogenous intensities on both T1 and T2-weighted images [24]. Areas of calcification and flow voids can be challenging to identify in classical MRI and can be seen well in susceptibility-weighted images (SWI). Different duration of haemorrhage within the lesion can be appreciated well on MR images. On gadolinium-enhanced T1-weighted MR imaging, tumour mass shows inhomogeneous contrast enhancement. Contrast MRI further helps in identifying subependymal enhancement, recurrence around previously operated sites and leptomeningeal spread. Imaging also helps to assess ventricular size as these tumours grow towards the ventricles and many patients develop secondary hydrocephalus. As there are no pathognomonic image findings of PCNS-NB, it should be kept in the differential diagnosis of any patients with the clinical possibility of PCNS-NB and intra-axial, intraventricular or periventricular mass lesion [24]. Primary CNS neuroblastoma is usually intra-axial and spread through CSF pathways, whereas secondary neuroblastoma is mainly extra-axial but can have haemorrhagic deposits in the parenchyma and sutural diastasis on CT due to epidural deposits [23].

#### **2.2 Histopathology**

Grossly PCNS-NB tumours are massive, discrete, firm, and cystic in appearance. Histopathology of a newly designated group of tumours as CNS neuroblastoma which were earlier designated as CNS neuroblastoma or CNS ganglioneuroblastoma in 2007 WHO classification scheme [8] showed distinct characteristics. CNS NB-FOXR2 showed an embryonal architecture with small cells and areas of differentiation in neuropil, neurocytic cells and ganglion cells with uniform expression of OLIG2 and neuronal antigen synaptophysin (**Figure 1**) [13, 18]. Histologically ganglioneuroblastoma consists of ganglion cells with different degrees of differentiation, Nerve sheath, glial fibres, and malignant neuroblastoma cells [9, 25–27]. Common pathological picture of ganglioneuroblastoma includes

**Figure 1.**

*Various routes for entry of neuroblastoma cells, and its spread to and within CNS.*

ganglion cells with a double nucleus, highly infiltrated and proliferated cells with dense chromatin [28, 29]. Further ganglioneuroblastomata have two histological subtypes: undifferentiated type has a small round to oval cells with hyperchromatic nuclei, and poorly differentiated type has a large round to oval spindle-shaped cells with pale staining nuclei [30, 31].

#### **2.3 Discussion**

Neuroblastoma is an enigmatic and one of the most common malignant solid tumour of the paediatric age group. Neuroblastoma is a disease with a grim prognosis, and the outcome has not changed significantly in the past two decades. Neuroblastoma teaches us essential aspects of CNS and neural crest development. Primary CNS Neuroblastoma (PCNS-NB) is a rare subtype of neuroblastoma with variable classification. It includes CNS neuroblastoma and ganglioneuroblastoma. In 2016 WHO classification of CNS tumours, PCNS-NB is classified as embryonal tumours. Embryonal tumours with the exception of medulloblastoma has been reclassified based on molecular alterations, for example atypical teratoid rhabdoid tumour (AT/RT) characterised by SMARCB1 or SMARCA4 inactivation, C19MC altered and/or LIN28A expressing embryonal tumour with multi-layered rosettes (ETANTR) and CNS neuroblastoma/Ganglioneuroblastoma without specific histological features or molecular alterations [8]. Based on global transcriptional and methylation profiling four tumour entities have been proposed: CNS neuroblastoma with FOXR2 activation (NB-FOX-R2), High grade neuroepithelial tumour with MN1 alteration (HGNET-MN1), high grade neuroepithelial tumour with BCOR alteration (HGNET-BCOR), and Ewing sarcoma family tumour with CIC alteration (EFT-CIC) [18]. CNS neuroblastoma rarely contains GFAP positive cells which are usually reactive astrocytes and most of the NB-FOX-R2 tumours are neuroblastic differentiation and contains neurocytic cells with poorly differentiated neuropil rich stroma and embryonal architecture [32]. However, there are reports of CNS neuroblastoma with GFAP positive tumour cells demonstrating both neuronal and glial nature, though the clinical significance of such entity is unknown [32]. Since, PCNS-NB is a rare entity and usually present in younger age group, little is known about its treatment protocols, prognostic factors and patient risk stratification. Review of literature suggests that PCNS-NB preferentially occurs in the supratentorial space with involvement of frontal and parietal region [4]. Clinical presentation of PCNS-NB is usually as per the most common site of involvement. Since, most of the PCNS-NB prefers supratentorial location preferably in the frontal and parietal region, patients

**69**

*Primary Central Nervous System Neuroblastoma: An Enigmatic Entity*

usually manifest with focal neurological deficits, bony lesions, irritative symptoms in form of seizures and symptoms of raised intracranial pressure due to mass effect. These effects of raised intracranial pressure and mass effect are less pronounced in infancy in younger children because of compensatory and adaptive mechanism of surrounding brain structures. Metastatic presentation of PCNS-NB is reported only in couple of cases via cervical lymph nodes and cerebrospinal fluid [33]. Therefore in evaluation of PCNS-NB complete screening neuroimaging of whole cranio-spinal neuroaxis should be performed to rule out any metastatic spread through the CSF. In general, PCNS-NB appears like other solid CNS tumours in brain MRI. They can be purely solid or solid-cystic. Solid component of tumours are T1 and T2 hypointense with mild hyperintensity on DWI sequences and inhomogenous contrast enhancement and increased relative cerebral blood volume (rCBV) on perfusion images. Cystic component of tumour appears hyperintense due to hyperproteieic content. MRS sequences show increase in choline peak and inversion of choline/NAA ratio, but none of these imaging parameters are unique to the PCNS-NB. It is essential to understand that there are no tumour markers or radiological markers which can reliably differentiate PCNS-NB from other tumours. Two essential criteria for defining PCNS-NB is presence of classical histology and absence of systemic neuroblastoma. The outcome of PCNS-NB depends on age, the tumour's aggressiveness, tumour

subtype, locations, histology and extension. Surgery is the treatment of choice, and adjuvant radiotherapy improves survival. Safety and outcome of radiotherapy are not well established in infants and younger population but need to be viewed in

Younger age group, a limited number of lesions, ganglioneuroblastoma subtype and surgical management, are found to be positive prognostic factors in PCNS-NB. Neuroblastoma has complex heterogeneous nature with varied prognosis, infants <1 year of age tend to have maximum overall survival with the tumour spontaneously regressing in some infants on the one hand and having widespread metastasis on the other hand [2, 12]. Studies have found best overall survival in infants <1 year of age and relatively less short term adverse events in age > 40 years with a 1-year

In the population-based studies, patients with extensive disease, multiple lesions, and metastasis were more often offered conservative management as surgical excision was not feasible [16]. Surgical excision is often referred to as the first line of management in the treatment of PCNS-NB, whenever feasible [4]. Differentiation in ganglioneuroblastoma lies in between malignant neuroblastoma and benign ganglioneuroma. Ganglioneuroblastoma subtype is found to be associated with a good prognosis. Studies show that the ganglioneuroblastoma subtype rarely infiltrates and tends to be localised with less incidence of metastatic deposits [16, 34]. This explains that patients with this subtype are likely to be offered surgery and benefit from surgical excision with overall better survival. Ganglioneuroblastoma typically has a high invasive behaviour but slower multiplication rate and the asymptomatic period of up to 60 months has been reported after

light of improved survival obtained by adjuvant radiotherapy.

**3. Summary and perspectives**

**3.1 Prognostic factors**

survival of 57.2% [16].

**3.2 Management options**

surgical excision [35, 36].

*DOI: http://dx.doi.org/10.5772/intechopen.98244*

#### *Primary Central Nervous System Neuroblastoma: An Enigmatic Entity DOI: http://dx.doi.org/10.5772/intechopen.98244*

usually manifest with focal neurological deficits, bony lesions, irritative symptoms in form of seizures and symptoms of raised intracranial pressure due to mass effect. These effects of raised intracranial pressure and mass effect are less pronounced in infancy in younger children because of compensatory and adaptive mechanism of surrounding brain structures. Metastatic presentation of PCNS-NB is reported only in couple of cases via cervical lymph nodes and cerebrospinal fluid [33]. Therefore in evaluation of PCNS-NB complete screening neuroimaging of whole cranio-spinal neuroaxis should be performed to rule out any metastatic spread through the CSF. In general, PCNS-NB appears like other solid CNS tumours in brain MRI. They can be purely solid or solid-cystic. Solid component of tumours are T1 and T2 hypointense with mild hyperintensity on DWI sequences and inhomogenous contrast enhancement and increased relative cerebral blood volume (rCBV) on perfusion images. Cystic component of tumour appears hyperintense due to hyperproteieic content. MRS sequences show increase in choline peak and inversion of choline/NAA ratio, but none of these imaging parameters are unique to the PCNS-NB. It is essential to understand that there are no tumour markers or radiological markers which can reliably differentiate PCNS-NB from other tumours. Two essential criteria for defining PCNS-NB is presence of classical histology and absence of systemic neuroblastoma.

The outcome of PCNS-NB depends on age, the tumour's aggressiveness, tumour subtype, locations, histology and extension. Surgery is the treatment of choice, and adjuvant radiotherapy improves survival. Safety and outcome of radiotherapy are not well established in infants and younger population but need to be viewed in light of improved survival obtained by adjuvant radiotherapy.
