The term 'Primitive neuroectodermal tumors (PNET)' may be used as a more descriptive term to encompass all forms of embryonal cell tumor, with additional references made to histology. It was originally intended to describe a smaller subset of highly undifferentiated neoplasms, also of neural tube origin. The majority of these embryonal tumors are found infratentorially in the form of cerebellar medulloblastomas.

Recently, WHO opted against this, retaining it instead for the purpose of referring to cerebellar medulloblastomas, irrespective of location. Medulloblastomas are discussed in this review.  Other embryonal tumors are discussed elsewhere.

Epidemiology:

They comprise 6% of all intracranial neoplasms, about 12 per cent of all neuroectodermal tumors and about 26 per cent of intracranial tumors in children. While the majority of medulloblastomas are encountered between the ages of 4 and 14 years, the first decade of life accounting for more than 50 per cent, they do occur in infants and in young adults.

There is a slight male preponderance. Though a number of authorities consider the tumor to be restricted to the pediatric age group, according to Rubinstein et al most a third of them occur between the ages of 15 and 35 years. 

Pathology:

Medulloblastoma is associated with several syndromes, and phakomatoses. 5% of Gorlin's syndrome (multiple nevoid basal cell carcinomas, multiple skeletal and cutaneous anomalies, calcification of the dura, hydrocephalus, and developmental delay) develop desmoplastic medullblastoma. It is an autosomal dominant disorder in which the defective gene is at chromosome 9q. In Turcot's syndrome (mutiple familial polyposis), the inheritance of the medulloblastoma is variable either autosomal recessive or dominant, with defective gene on chromosome 5q21. Other associated syndrome include, Li-Fraumeni syndrome, and Ataxia-telangiectasia.

However, no specific genetic abnormality or growth factor has been consistently associated with its pathogenesis.

In 50% of them the chromosome 17p is absent. An isochromosome of the long arm of 17q is thought to be related to tumor progression. The hsNF5 gene on chromosome 22 has been found to be altered in sporadic medulloblastomas and PNETs (atypical teratoid -rhabdoid tumors of the cerebellum).

The medulloblastoma is an almost exclusively cerebellar tumor, made up of primitive, poorly differentiated cells. While most investigators, concede at least a neuroepithelial origin to the medulloblastoma, some believe that there is no such tumor entity, it being merely an intermediate stage in the development of an astrocytoma, an oligodendroglioma or an ependymoma. 

It is generally conceded that there is no such cell as the medulloblast, and the tumor possibly arises from the fetal external granular layer of the cerebellar cortex, which normally persists till the age of one year.

In older children and adults, the tumor may possibly originate from the inner granular layer.

Alternate cells of origin of the cerbellar medulloblastoma are the persisting cell nests in the posterior or anterior medullary velum. 

Thus the medulloblastoma might arise from any of these germinative cell groups, anywhere along their migratory path.  This would determine the location of these tumors in terms of a midline or a more lateral situation, the former occurring at an earlier age, as the migration of these primitive cells from the roof of the fourth ventricle would occur sooner to the vermian cortex than to the more distant lateral cortex. Hemispheric involvement is more frequent in adults.

The gross appearance of the tumor is of some neurosurgical and practical importance.  The more cellular midline tumors of childhood often appear circumscribed, are white, soft and friable, while the hemispheric tumors of adult age are firm or even had to feel, darker and often plaque-like over the cerebellar cortical surface.  The former may be found extending into the fourth ventricle and create doubts about an ependymoma. The latter may present as a surface tumor simulating a meningioma or as a mass in the cerebellopontine angle mimicking a schwannoma. 

A frequent histopathologic change in medulloblastomas is their tendency to develop a rich reticulin frame work when they reach the surface of the cerebellum, constituting a truly ‘desmoblastic’ change(20%). This may closely resemble the entity, described as arachnoid sarcomas of the posterior fossa. On contacting the highly vascular piaarachnoid, the medulloblastoma develops a moderate to profuse mass of reticulin fibrils among the tumor cells.  The desmoblastic tumors occur in patients with a significantly higher mean age (21 years) and are in the cerebellar hemisphere. 

Electron microscopic examination of medulloblastomas reveals large closely apposed cells with occasional desmosomes pointing to the primitive nature of the cells. While microtubules were detected within these as in other primitive neuroepithelial tumors, synaptic structures have not been encountered.

Metastasis, generally arising by seeding of the parent tumor in the neuraxis is well known, with 25% incidence at autopsy.

2% to 7% metastasize extracranially, the commonest site being the bone. Other sites include, the lymphatic spaces, peritoneum, lungs, and liver.

Clinical Features:

Features of raised intracranial pressure is the presenting symptom. There is an higher frequency of hydrocephalus in children due to higher incidence if vermian involvement. Unsteady gait, ataxia, and decreased coordination are other features. rarely, there may be an head tilt (due to diplopia related to sixth nerve palsy) or torticollis (secondary to pain because of dural traction).

Standard therapy for medulloblastoma is surgical resection, followed by craniospinal radiation. Supratentorial PNETs are staged and treated the same way.

Radical resection is possible in the majority. The aim is to establish diagnosis, and restore CSF pathways. Although the spread of tumor cells along the shunt appears to be unfounded, current trend is to avoid a prior shunt procedure for the common (75%) associated hydrocephalus. An extraventricular drainage at the time of tumor resection helps.

A transvermian approach, through a vertical incision over the lower vermis, is widely practiced.

Cerebellomedullary fissure approach avoids vermian incision. This approach involves opening the fissure between the tonsil and medulla, the PICA (posterior inferior cerebellar artery) is in close proximity. The fissure is widened by lifting the tonsil off the medulla, the choroid plexus is visualized with the tumor anterior to it. The fissure is widened  on both sides for a better exposure.

Transforamen magendie approach is ideal for large tumors (65%), which grow through the foramen and occupy the space between tonsils and the cisterna magna.

Meticulous debulking of the tumor followed by dissection from the surroundings is carried out. The part of the tumor covering the brainstem (30% of the tumors are adherent to the brainstem), should be removed last, because the large space created by tumor excision enhances the visibility.

Incidence of post operative new neurological deficits have been reported to be in the range of 28% to 44%. Abducent and facial nerve palsy, worsening of cerebellar dysfunction, bulbar palsy, brainstem injury are the possibilities. These are labeled as the 'fourth ventricle syndrome'. In the majority, the deficits do not recover. Post operative seizures can occur in about 7% of cases.

'Cerebellar mutism' following posterior fossa surgery was initially described by Hirsh in 1979, and occurs in 5% to 30% of cases, usually in children. Classically, it occurs on 1 to 2 post op days. There is irritability, decreased verbal output, and behavioral disturbances, global cerebellar dysfunction, and weakness of limbs. Cranial neuropathies can occur. This is self limiting and recovery takes 4 days to 4 months. In majority the recovery is not complete and require long term supportive care.

The damage to the dentate nucleus and the dentate-thalamo-cortical connection seems to be the cause, as it happens more commonly after excision of large vermian lesions, necessitating incision and retraction of the dentate nucleus. Patients with brainstem tumor involvement are at a higher risk. SPECT studies reveal hypoperfusion of the thalamus, medial frontal lobe, and the frontotemporal-parietal regions in the acute phase.

Standard treatment includes radiotherapy. 5 year survival rates of 50% to 70% with 5400 to 5800cGy administered to the posterior fossa and 3500cGy to the neuroaxis have been reported. Attempts, such as hyperfractionated irradiation and dose reduction, have been made to decrease cognitive deficits associated with craniospinal irradiation in patients younger than 3 years old; they resulted in increase in relapses. More recent attempts include the use of chemotherapy with encouraging results.  Focal radiation and stereotactic radiosurgery have been  shown to be acceptable adjuvants to conventional irradiation.

Additionally, chemotherapy in patients with incomplete resection, or with metastasis, improves the 5 year survival rates to 90%, and in those with metastasis to 50%. Various chemotherapy regimens in association with radiotherapy have been tried. Recently, it has been reported that, vincristine weekly during radiotherapy and then vincristine, cisplatin, and CCNU for eight cycles afterwards, substantially improves survival. New agents that have shown promise in laboratory models of these tumors, are being studied in patients. In addition, the use of blood stem cells to permit high dose chemotherapy that would otherwise cause dangerously low blood counts is being explored. Shorter, more intensive chemotherapy is currently being tested in children. Studies are on to see the effectiveness of chemotherapy to delay the radiotherapy in the young children.

To summarize, the widely recommended regimen include,

   1) Surgery and craniospinal radiation in those above 3 years old.

       Chemotherapy is added in those with residual tumor and in those with metastasis.

   2) Surgery in those under 3 years old; radiotherapy is delayed until 3 years old.

       Preirradiation chemotherapy may be considered.

Outcome:

Age at diagnosis and presence of spread decides the survival. Patients under 3 years of age belong to poor risk.

Duration of symptoms, severity of hydrocephalus, tumor size, and even brainstem invasion do not correlate with survival.

The extent of tumor resection does influence the survival significantly, especially in standard risk patients (the patients older than 3 years with no evidence of metastasis). Those with residual tumor volume of less than 1.5cm² have shown improved 5year progression free survival in 77%, compared with 53% in those with more than 1.5cm² of residual tumor.

None of the biological indicators, such as GFAP, DNA ploidy, have been shown to correlate with outcome consistently.

Treatment sequelae include, cognitive and neuropsychological dysfunction, endocrinopathy, and secondary malignancy. Progressive decline in overall intelligence is noted in almost all children, especially under 7 years old, receiving craniospinal radiation. It is most evident 2-3 years after treatment. Many long term survivors suffer psychological difficulties in their adult years. Growth retardation, thyroid dysfunction, delayed puberty, and adrenocortical insufficiency may also occur.

Second malignancies, have occurred 6-7 years after initial therapy, and 50% are in the radiotherapy field. Acute leukemia has been reported in children treated with craniospinal radiation and chemotherapy.

Recurrence is usually incurable. Treatment of recurrence include resurgery and a variety of chemotherapeutic agents. Use of stem cells and even bone marrow transplantation have been tried with some success.

Those with asymptomatic recurrences survived longer than those with symptomatic recurrences. The majority of recurrences present within the first two years. Aggressive surveillance with brain and spinal MRI is recommended. Those who had no recurrence after 8 years, can be considered cured.