Definition and newclassification of primitive neuroectodermal tumor. Clinical presentations and methods of diagnosis. Different lines of treatment

2. Medhat Mustafa, MD,
Department of Neurosurgery
Suez Canal University, Ismailia, Egypt

3. Primitive
Neuroectodermal
Tumor

4. Objectives
Identify the etiology of primitive
neuroectodermal tumor medical conditions and
emergencies.
Outline the evaluation of primitive
neuroectodermal tumor
Review the management options

5. Background
Primitive neuroectodermal tumors (PNET) are
neoplasms of which medulloblastoma is the
prototype. These are small cell, malignant
embryonal tumors showing divergent
differentiation of variable degree along
neuronal, glial, or rarely mesenchymal lines.

6. Background
The most recent WHO categorization of embryonal
tumors is as follows:
• Medulloblastoma
• CNS primitive neuroectodermal tumor (PNET):
◦ CNS neuroblastoma
◦ CNS ganglioneuroblastoma
◦ Medulloepithelioma
◦ Ependymoblastoma
• Atypical teratoid/rhabdoid tumor

7. Introduction
Primitive Neuroectodermal Tumors (PNETS) of
the central nervous system (CNS-PNETs) are
identified as highly aggressive large tumors that
are found in the brain and spine

8. Introduction
CNS PNETs can be distinguished from PNETs
occurring outside the central nervous system
(referred to as peripheral PNETs).

9. Introduction
PNET of the CNS can be divided grossly into
infratentorial tumors (medulloblastoma or
iPNET) and supratentorial tumors (sPNET).

10. Pathophysiology
Considerable controversy exists regarding the
histogenesis of these tumors. Initially, these
dense, cellular, embryonal tumors were thought
to have a common origin from primitive
neuroectodermal cells and to differ only in their
location, type, and degree of differentiation

11. Pathophysiology
In the revised World Health Organization (WHO)
classification, however, many of these tumors
are given a separate niche on the basis of the
assumption that these embryonal tumors also
could arise from cells already committed to
differentiation

12. Pathophysiology
In 2016, the World Health Organization (WHO)
published a revised classification of central
nervous system (CNS) tumors using molecular
parameters

13. Pathophysiology
In this classification, some tumors previously
recognized in the 2007 classification had been
renamed or eliminated
The primitive neuroectodermal tumor is no
longer recognized as such and those tumors are
now under the classification of embryonal
tumors

14. Pathophysiology
CNS embryonal tumors are now classified
using specific genetic/molecular characteristics
Medulloblastomas are the most common
embryonal tumors and have their own
genetic/molecular defined groups

15. Pathophysiology
addition to their histologically defined groups
(classic, desmoplastic/nodular, medulloblastoma
with extensive nodularity, and large
cell/anaplastic).
A combination of the genetic profile and the
histology determines the prognosis of these
tumors

16. Epidemiology
Primary CNS tumors are the second most
common tumor in children and adolescents
after leukemia
Approximately 20% of pediatric brain tumors
are CNS embryonal tumors

17. Epidemiology
This number includes all the medulloblastomas
and all other embryonal tumors
Embryonal tumors are the most common CNS
tumor in children aged 0–4 years (13.1%), and
the fifth most common in children and
adolescents age 0 to 19 years (10.1%)

18. Epidemiology
The CNS embryonal tumors have a preference
for children below the age of 4 and are more
common in females
Supratentorial embryonal tumors are found in
older children with a mean age of 8.4 years,
with a 2.3:1 female to male predominance

19. Histopathology
All embryonal tumors are classified as WHO IV
The genetic/molecular analysis of each tumor is
essential
The histopathological changes are still important
for the initial recognition of the tumor and the
intraoperative consultation.
Immunohistochemical staining shows specific
characteristics in each tumor

20. Histologic Findings
Primitive cells are observed growing in sheets or
cords of dense cellularity with increased mitotic
index and increased nuclear-cytoplasmic ratio

21. Histologic Findings
Formation of Homer-Wright rosettes (ie,
neuroblastic rosettes consisting of tumor cell
nuclei disposed in a circular fashion about
tangled cytoplasmic processes) is typical but not
always seen and is not essential for diagnosis.
When present, it is frequently associated with
marked nuclear pleomorphism and high mitotic
activity

22. Histologic Findings
Associated gross pathologic findings may include
cystic changes, although the tumors are usually
solid. They may vary from soft to firm in
consistency. Geographic areas of necrosis,
vascular proliferation, or calcification are less
common, while hemorrhage is rare

23. Histologic Findings
Immunohistochemical markers can confirm
differentiation toward astrocytic or neuronal
lineage.
Unusual variants include those with melanin
deposition, rhabdomyoblastic differentiation, or
desmoplastic features, among others.

24. History and Physical
The location of the tumor, supratentorial or
infratentorial, is important for the manifestation
of symptoms.

25. History and Physical
Those with an infratentorial location usually
develop hydrocephalus with headache,
vomiting, irritability, and lethargy. Ataxia or
other cerebellar signs and cranial nerve palsies
are common.
They rarely have seizures

26. History and Physical
In supratentorial locations, vomiting, seizures,
and headaches are common. Hemiparesis is
present if the tumor affects the cortical motor
areas or the descending tracts

27. History and Physical
The presentation is also affected by age.
Younger patients present irritability, vomiting,
and visual problems.
Those older than three years usually show
headaches, vomiting, and ataxia

28. History and Physical
These aggressive tumors have a short
prediagnosis interval between the first
symptoms and the radiological diagnosis, with a
median of 20 days.
Infratentorial tumors, high-grade tumors, and
those in younger patients have the shortest
intervals.

29. Causes
Isolated PNET is sporadic in nature, and only 14
familial cases have been reported in the
literature.
Loss of the short arm of chromosome 17
(17p13.3) is the most frequent abnormality
(particularly with
medulloblastoma, in which it is found in 30-40%
of cases),

30. Causes
Studies on molecular characterization have
identified 4-6 subgroups of medulloblastoma on
the basis of molecular differences

31. Causes
The most current international consensus
recognizes 4 core medulloblastoma subgroups
namely, SHH, WNT, Group 3, and Group 4.
This is adopted based on the knowledge of
genomic complexity of medulloblastoma as
analyzed by recent high-throughput genomic
technology

32. Causes
Karyotypically, almost all PNETs are abnormal.
Certain conditions have increased associations
with PNETs
They include the following
Gorlin syndrome,
Turcot syndrome
Li-Fraumeni syndrome

33. Imaging Studies

34. MRI
MRI is the imaging technique of choice. The
typical tumor is a heterogeneous mass with ill-
defined margins
arising from the vermis, which fills the fourth
ventricle.
Typical findings include moderate to intense
enhancement of the tumor, which is not
homogenous

35. MRI
Some tumors can show areas with blood
products, microcalcifications, and necrotic-cystic
components
They have restricted diffusion due to the high
cellularity of the tumor. These characteristics are
similar to high-grade gliomas, making molecular
diagnosis very important

36. MRI
Magnetic resonance spectroscopy shows a
choline peak with reduced N-acetyl-aspartate
and a high ratio of choline/aspartate.
Spinal MRI is usually required for the detection
of seeding and prognosis

37. Cerebellar medulloblastoma.
This MRI (axial view, T2-
weighted image) demonstrates
the heterogeneity of the
tumor.

38. MRI
Cerebellar medulloblastoma.
This sagittal view MRI
without contrast
demonstrates characteristic
midline
cerebellar location with mild
obstructive hydrocephalus.

39. MRI
The entire neuraxis should be imaged to detect
spinal metastases, which may occur via
subarachnoid dissemination

40. CT scan
In emergent situations, CT scan is preferred over
MRI because of its easy accessibility. However,
CT scan resolution is inferior to that of MRI. The
mass is typically midline, relatively
heterogeneous, and variably contrast enhancing

41. CT scan
Cerebellar medulloblastoma.
This axial view CT scan with
contrast shows a partially
enhancing mass arising in the
midline from cerebellum and
filling the fourth ventricle.

42. Treatment
The current most effective therapy in these
tumors is triple therapy, which is surgical
resection plus radiation and chemotherapy

43. Treatment / Management
Gross total resection is always attempted as it
provides better outcomes
For persistent lesions, second-look surgery is
recommended to remove residual tumor

44. Treatment / Management
Available studies have failed to show a
significant advantage, in terms of event-free
survival, of total resection as compared to near-
total and less-aggressive resections.
.

45. Treatment / Management
Craniospinal radiation is usually given due to the
high incidence of distant leptomeningeal
metastases and spinal seeding.

46. Treatment / Management
Permanent CSF diversion in the form of
ventriculoperitoneal shunt is required in as
many as 30% of these cases

47. Treatment / Management
Chemotherapy varies with each protocol, but a
combination of vincristine, cisplatinum,
cyclophosphamide, etoposide is common
Myeloablative chemotherapy has been used in
some cases, followed by hematogenic stem cell
rescue.

48. Treatment / Management
Ongoing worldwide research has explored
nonconventional therapeutic strategies such as
immunotherapy and gene therapy to improve
outcome and survival, although their clinical
efficacy is yet to be established

49. Treatment / Management
Moreover, there is growing interest in proton
therapy as a potential replacement for photon
therapy, while high-dose chemotherapy and
autologous stem cell rescue may improve
therapeutic efficacies

50. Prognosis
The following factors worsen the prognosis:
Presence of metastases at diagnosis
Infiltrative nature, evidence of glial
differentiation, and presence of TP53 mutation
Recent genomic study reveals that cases in the
WNT group showed a slightly better survival
with more favorable prognosis than those in the
SHH or non-WNT/SHH group

51. Prognosis
Unfavorable location that prevents complete
resection: Failure at the primary site continues
to be the predominant barrier to cure in
patients with medulloblastoma.

52. Prognosis
Younger age at presentation: Age older than 4
years at the time of initial diagnosis is associated
with more favorable prognosis than age younger
than 4 years.

53. Prognosis
In recent series of low-risk cases, the 5-year
survival rate has been reported to be 60-80% (or
even higher).
Many tumors relapse at a period equal to the
age at diagnosis plus 9 months (the Collin law

54. Complications
These tumors impose a severe burden on the
patient, and many significant complications
occur as a consequence of the tumor and the
triple therapy received.

55. Complications
Surgery is challenging and sometimes tricky.
Radiation and chemotherapy contribute to
substantial morbidity due to the ionizing
radiation's effects and the adverse effects of the
chemotherapeutic agents.