OVERVIEW: What every practitioner needs to know
Are you sure your patient has a medulloblastoma or primitive neuroectodermal tumor? What are the typical findings for this disease?
Primitive neuroectodermal tumors (PNET) are a diverse group of highly malignant, “small round blue cell” tumors and are biologically distinct. They are divided into peripheral PNET and central nervous system (CNS) PNET. The former are unrelated to brain tumors and part of the Ewing sarcoma family of tumors, whereas the latter are primary brain tumors. This chapter focuses on those in the CNS. These tumors, also called embryonal tumors, are grade IV cancers by the World Health Organization (WHO) classification and can disseminate throughout the CNS and rarely systemically.
PNET are best identified by tumor location, patterns of differentiation, and molecular findings. Histological examination with conventional hematoxylin and eosin staining reveals small round blue cells with poor differentiation and high mitotic activity. Nevertheless, all these CNS embryonal tumors are likewise biologically distinct.
Embryonal neoplasms include medulloblastoma, atypical teratoid/rhabdoid tumor (ATRT), pineoblastoma, ependymoblastoma, cerebral neuroblastoma, medulloepithelioma, and supratentorial primitive neuroectodermal tumor.
Medulloblastoma (MB) is the most second common pediatric brain tumor and occurs specifically in the cerebellum. As with all brain tumors in the CNS, presentation is often dependent on location of the mass itself.
Medulloblastoma presentation is often due to hydrocephalus and its cerebellar location. Thus symptoms include headache, nausea, vomiting as well as head tilt, cranial palsies, and imbalance. If there are metastases then back pain may be a complaint. On exam, papilledema, ataxic gait, and dysmetria (finger-to-nose incoordination) predominate. Up to 30% of patients present with leptomeningeal dissemination at the time of diagnosis.
Supratentorial PNET in the cerebrum may present with signs of hydrocephalus along with seizures, hemiparesis, and hemisensory complaints depending on anatomical location.
Pineoblastoma occurs in the pineal region and therefore Parinaud’s syndrome (paralysis of upgaze, light-near dissociation, convergence-retraction nystagmus) and signs and symptoms of hydrocephalus are common.
Spinal cord PNET presents with back pain and incontinence. Rarely, scoliosis can be the presenting symptoms in those with long-standing spine pathology.
Symptoms can last days to months though usually not greater than 6 months.
Infants may present with increasing head circumference, bulging fontanelles, and irritability.
What other disease/condition shares some of these symptoms?
A multitude of other brain tumors can mimic PNET. Ependymoma and astrocytoma (WHO grade I-IV) can present in the spine and cerebrum. Germ cell tumors, pineocytoma, and pineal cysts can also occur in the pineal region like pineoblastoma.
Tumors that also commonly occur in the cerebellum other than MB are ependymoma (WHO II-III) and pilocytic astrocytoma (WHO I). Choroid plexus tumors, though rare, can also present in the cerebellum along the fourth ventricle. Hemangioblastoma may occur in the cerebellum of the older child, and be the harbinger of von Hippel-Lindau disease.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
As with any signs of increased intracranial pressure or neurologic deficits, a computed tomography (CT) scan of the head is essential to evaluate for a mass. If one is found, magnetic resonance imaging (MRI) of the brain and spine with and without gadolinium is indicated if the patient is stable. Otherwise, neurosurgical intervention for a patient in extremis from hydrocephalus is warranted. Diagnosis cannot be confirmed without histologic evaluation.
It is important to differentiate MB from ATRT with careful pathologic review and fluorescence in situ hybridization (FISH) studies. ATRT has deleted or absent INI1 genes by immunohistochemistry and FISH, and has a worse prognosis than MB and other PNET.
Would imaging studies be helpful? If so, which ones?
As stated above, neuroimaging is required for initial diagnosis. On non-contrast CT, any PNET oftens appears as a hyperdense mass and can have calcifications and intratumoral hemorrhage. MRI of the brain and spine is essential for staging and assessment. MRI with gadolinium contrast reveals a heterogenously-enhancing tumor that is hypodense on T1 and hyperintense on T2/FLAIR with vasogenic edema and mass-effect. Metastasis and leptomeningeal disease will contrast enhance as well. PNET are often diffusion positive on diffusion weighted imaging (DWI) due to its compact cellularity.
If you are able to confirm that the patient has medulloblastoma or a primitive neuroectodermal tumor, what treatment should be initiated?
If a brain tumor is suspected, the child should be in the care of a multi-disciplinary team that can provide neurosurgical, neuro-oncologic, and neurologic support. Maximal surgical resection of the primary tumor influences outcome. Tumors that can be gross totally resected (as noted on post-operative MRI) and have no signs of dissemination have the best prognosis. MB requires radiation and chemotherapy for potential cure,
In general, children are enrolled in large multi-institutional clinical trials if available to improve treatment regimens and overall survival (OS).
MRI of the brain and spine to evaluate for metastasis is necessary for staging. After maximal tumor resection, a lumbar puncture is performed 10-14 days post-surgery. The spinal fluid is analyzed for microscopic evidence of tumor cells. Both MRI and spinal fluid cytology are necessary for staging for treatment.
MB is divided into average-risk and high-risk categories. Patients with average-risk MB that have had a gross total resection on MRI, no metastasis radiographically or on CSF have up to an 80% OS. Those with high-risk have residual disease or signs of leptomeningeal spread (50-60% OS).
Recent advances in histology and molecular markers are being employed to categorize risk assessment as well. Tumors with ß-catenin nuclear immunoreactivity, mutations in the sonic hedgehog pathway, Wnt signaling pathway, or nodularity on histology are thought to have a better prognosis. Those with elevated c-myc expression or large-cell anaplasia have a poor prognosis. In the years ahead, these advances may supplant the current categorization of high- and average-risk.
After surgical resection, MB requires craniospinal radiation (CSI) with a higher radiation dose to the tumor bed/posterior fossa. For average-risk patients, radiation doses for CSI vary from 1800-2400 centigray (cGy) whereas for high-risk MB, CSI is generally 3600 cGy. Total radiation boost to the posterior fossa, typically using conformal techniques to limit the volume to the tumor and spare the cochlea and middle cranial fossa, averages 5400 cGy in both categories. Areas with spinal metastases are generally given a higher dose of radiation as well.
Chemotherapy may accompany radiation depending on trial recommendations and risk assessment. Vincristine is commonly given weekly with radiation in average-risk MB. Those with high-risk disease may be given additional chemotherapy (carboplatin) with radiation as part of a group study to improve outcome.
After radiation therapy, chemotherapy is alkylator-based, with cisplatin, and CCNU or cyclophosphamide, in conjunction with vincristine. Etoposide orally or intravenously can be added. High-dose chemotherapy with autologous stem-cell rescue or the addition of biologic agents to improve OS can also been implemented as part of large cooperative trials.
In children less than 3 years of age, radiation can cause significant neurocognitive decline and endocrinopathies from its long-term effects. Thus, protocols with only chemotherapy are used to avoid the long-term ramifications of radiation therapy. Methotrexate is used increasingly for infant medulloblastoma in addition to the traditional chemotherapies stated above.
Primitive neuroectodermal tumor
As stated above, resection and staging with MRI and CSF analysis should be performed. Spinal fluid cytology by lumbar puncture, not ventricular sampling, is assessed 10 to 14 days after surgery, to minimize the confounding effects by postsurgical cellular debris.
Multi-institutional trials are recommended for these diagnoses if possible especially since outcome can be poor. ATRT generally has a poor prognosis and pineoblastoma is a particularly difficult tumor to treat. As these tumors are both rare, there are collaborative efforts to improve outcome.
All PNETs require radiation and chemotherapy for optimal survival. Treatment is similar to that of high-risk medulloblastoma.
Chemotherapy-only regimens are recommended for those less than 3 years of age. The role of high-dose myeloablative chemotherapy with autologous peripheral blood stem cell rescue remains investigational. Whether this approach improves chance of survival is controversial, although toxicity is higher.
What are the adverse effects associated with each treatment option?
Radiation therapy can cause a host of acute and long-term effects. Acutely, children can have local skin irritation, hair-loss, nausea, vomiting, and fatigue. Somnolence syndrome in the midst or end of radiation can occur and last for weeks to months.
Long-term effects are being recognized and include: vasculopathies, cognitive decline, and secondary malignancies. These are seen within 1 to many years following treatment and may be compounded by chemotherapy as well. Younger children are at higher risk for cognitive decline. Neuropsychologic testing is often performed during and after treatment to assess educational needs.
Chemotherapy also has short term and long-term ramifications. During treatment, chemotherapy can cause bone marrow suppression, neuropathy, alopecia, and weight loss. Thus, children require tranfusions for thrombocytopenia and anemia and have an increased risk of infections from neutropenia. Vincristine causes peripheral neuropathy (foot drop, hand weakness) and constipation. Residual effects of neuropathy can be life long and children may require orthotics for gait issues. Cisplatin can affect kidney function and thus electrolyte imbalance is common.
Unfortunately, hearing can be directly affected by both cisplatin and radiation, and audiograms are necessary throughout treatment and thereafter. The need for hearing devices are not uncommon. Survivors may also face fertility issues and increased risk of secondary malignancies.
Late effects of chemotherapy are well detailed in the Children’s Oncology Group Long-Term Survivorship Follow-Up Guidelines at www.survivorshipguidelines.org.
What are the possible outcomes of primitive neuroectodermal tumor/medulloblastoma?
Prognosis is dependent on the type of PNET, surgical resection, and evidence of metastasis. As stated above, average-risk MB has an 80% OS whereas high-risk MB averages 60% OS.
Without treatment, survival is dismal. Currently, radiation and chemotherapy are standard of care and offer the best outcome for PNET. Radiation is avoided in those less than 3 years to prevent severe neurocognitive decline. With the new advancements in molecular stratification, efforts are being made to tailor treatments on risk assessment and reduce long-term effects.
What causes this disease and how frequent is it?
The incidence of childhood CNS neoplasms is approximately 3.5 per 100,000 children/year and MB is just less than 20% of these cases. It is the second most common pediatric brain tumor after pilocytic astrocytoma. Peak occurrence is around 4 years of age with 30% of cases over 15 years of age. Boys are more affected than girls.
The etiology is not known except in rare cases with a germline mutation of a tumor suppressor gene. Gorlin syndrome is a constellation of nevoid basal cell carcinoma, jaw cysts, palmar and plantar pits, rib anomalies, hyporesponsiveness to parathyroid hormone, and MB. Other rare syndromes associated with MB include: Turcot syndrome, Li-Fraumeni syndrome (p53 mutation), ataxia telangectasia, or Coffin-Siris syndrome.
How do these pathogens/genes/exposures cause the disease?
Currently, it is unknown how these genes trigger the formation of embyronal tumors.
What complications might you expect from the disease or treatment of the disease?
Other than those discussed above with radiation and chemotherapy, neurologic issues may remain. These include seizures, leukoencephalopathy, headache, and imbalance.
How can primitive neuroectodermal tumor/medulloblastoma be prevented?
Unfortunately, there is no way to prevent brain tumors in children other than avoid exposure to radiation.
What is the evidence?
Duffner, PK, Horowitz, ME, Krischer, JP. “Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors”. N Engl J Med. vol. 328. 1993. pp. 1725-1731.
Cohen, BH, Zeltzer, PM, Boyett, JM. “Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial”. J Clin Oncol. vol. 13. 1995. pp. 1687-1696.
Zeltzer, PM, Boyett, JM, Finlay, JL. “Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children’s Cancer Group 921 randomized phase II study”. J Clin Oncol. vol. 17. 1999. pp. 832-845.
Packer, RJ, Goldwein, J, Nicholson, HS. “Treatment of children with medulloblastoma with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group study”. J Clin Oncol. vol. 17. 1999. pp. 2127-2136.
Tarbell, NJ, Friedman, H, Kepner, J. “Outcome for children with high stage medulloblastoma: results of the Pediatric Oncology Group 9031”. Int J Radiat Oncol Biol Phys. vol. 48. 2000. pp. 179
Pomeroy, SL, Tamayo, P, Gassenbeek, M. “Prediction of central nervous system embyronal tumour outcome based on gene expression”. Nature. vol. 415. 2002. pp. 436-422.
Gilberton, R. “Paediatric embryonic tumours: biological and clinical relevance of molecular genetic abnormalities”. Eur J Cancer. vol. 38. 2002. pp. 675-685.
Gajjar, A, Hernan, R, Kocak, M. “Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma”. J Clin Oncol. vol. 22. 2004. pp. 984-993.
Rutkowski, R, Bode, U, Deinlein, F. “Treatment of early childhood medulloblastoma by postoperative chemotherapy alone”. N Engl J Med. vol. 352. 2005. pp. 978-986.
Packer, RJ, Gajjar, A, Vezina, G. “Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma”. J Clin Oncol. vol. 24. 2006. pp. 4202-4208.
Northcott, PA, Korshunov, A, Witt, H. “Medulloblastoma compromises four distinct molecular variants”. J Clin Oncol. vol. 29. 2011. pp. 1408-1414.
Ongoing controversies regarding etiology, diagnosis, treatment
Large collaborative national and international efforts are underway to better characterize molecular characteristics of PNET and to improve treatment regimens.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has a medulloblastoma or primitive neuroectodermal tumor? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has medulloblastoma or a primitive neuroectodermal tumor, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of primitive neuroectodermal tumor/medulloblastoma?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- What complications might you expect from the disease or treatment of the disease?
- How can primitive neuroectodermal tumor/medulloblastoma be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment