Primitive Neuroectodermal Tumor.pptx

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

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

2. Primitive Neuroectodermal Tumor

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

4. 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.

5. 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

6. 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

7. Introduction C NS PNETs can be distinguished from PNETs occurring outside the central nervous system (referred to as peripheral PNETs).

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

9. 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

10. 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

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

12. 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

13. 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

14. 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

15. 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

16. 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 %)

17. 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

18. 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

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

20. 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

21. 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

22. 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.

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

24. 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

25. 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

26. 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

27. 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.

28. 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),

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

30. 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

31. 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

32. Imaging Studies

33. 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

34. 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

35. 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

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

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

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

39. 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

40. 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.

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

42. 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

43. 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. .

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

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

46. 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.

47. 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

48. 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

49. 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

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

51. 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.

52. 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

53. 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.

54. 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.