Primitive neuroectodermal tumor

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Gertrude Djouka, M.D.[2], Maria Fernanda Villarreal, M.D. [3]

Synonyms and keywords: Primitive neuroectodermal tumors; PNET; CNS PNET; Askin tumor; Peripheral neuroepithelioma; Ependymoblastoma

Overview

Primitive neuroectodermal tumor (also known as "PNET") is a rare type of malignant tumor originating from neuroectoderm. Neuroectoderm is normally involved in the development of the nervous system. Apart from central nervous system (CNS), PNETs can involve other tissues originating from the neuroectoderm such as muscles and bones. PNET was first discovered by James Ewing, an American pathologist, in 1921. However, the term PNETs was more commonly described in 1973 by Hart and Earle. In fact, PNETs are members of the Ewing tumor family. Primitive neuroectodermal tumor are classified into 3 subtypes. Histopathologically, PNETs should be differentiated from other tumors causing small round blue cell tumors involving bone and soft tissue. PNETs are more common among children. Clinical presentation of primitive neuroectodermal tumors is often non-specific and depend on the site of the tumor. Physical examination may be remarkable for papilledema, strabismus, nystagmus, imbalance, motor weakness, facial sensory loss, third, fourth, and sixth cranial nerve palsies, hemiplegia, hepatosplenomegaly, and adenopathy. On CT, findings associated with the diagnosis of PNETs, may include a large irregular mass with heterogeneous contrast enhancement. On MRI, findings of the PNETs may include highly variable and can be hypo-intense to isointense, but usually, hypo-intense on T1-weighted images and high signal solid components on T2-weighted images. For the management of peripheral form of PNET, systemic chemotherapy has been associated with a better prognosis and is generally recommended.

Historical Perspective

• Primitive neuroectodermal tumor was first discovered by James Ewing, an American pathologist, in 1921.
• In 1983 the term PNET was first used by Rorke to describe all undifferentiated CNS tumors with neuroepithelial origin, irrespective of their site.

Classification

• Primitive neuroectodermal tumor may be classified into 3 sub-types:
  • Central primitive neuroectodermal tumors (PNETs) which include tumors of CNS origin.
  • Peripheral primitive neuroectodermal tumors (pPNETs) which include tumors with soft tissue and bone origin. These tumors are also called Ewing family of tumors (EFTs) and classified into Ewing sarcoma, malignant peripheral primitive neuroectodermal tumors, Askin tumor, and less common tumors (eg, neuroectodermal tumor, ectomesenchymoma, peripheral medulloepithelioma).
  • Neuroblastoma which is derived from the autonomic nervous system.

Pathophysiology

• The pathogenesis of peripheral primitive neuroectodermal tumor is characterized by the chromosomal translocation t(11;22)(q24q12).
• This translocation fuses the EWS gene on chromosome 22 with the FLI1 gene on chromosome 11.
• The EWS-FLI1 gene has been associated with the development of PNET involving the synthesis of adrenal pathway.
• On gross pathology, white, hemorrhagic and necrotic mass are characteristic of PNET.

Courtesy of image Wikipedia

• On microscopic histopathological analysis, characteristic findings of the primitive neuroectodermal tumor, include small blue cell tumor with abundant mitotic figures, Homer-Wright rosettes, in which tumor cells surround neutrophils, fibrosis, and short and round or spindle-shaped nuclei.
• Immunohistochemical analysis can also be positive for CD99, CD56, Neuron-specific enolase (NSE), S-100 protein, synaptophysin, and chromogranin A.

Differentiating Primitive Neuroectodermal Tumor from Other Diseases

• Primitive neuroectodermal tumor must be differentiated from other diseases that cause seizures or an increase in intracranial pressure, such as astrocytoma, ependymoma, oligodendroglioma, intracranial teratoma, meningitis, encephalitis, and other brain tumors.
• Histopathologically, primitive neuroectodermal tumors should be differentiated from other tumors causing small, round, blue cell tumors involving bone and soft tissue, including lymphoma, small cell osteosarcoma, undifferentiated neuroblastoma, desmoplastic small round cell tumors, mesenchymal chondrosarcoma, rhabdomyosarcoma, and poorly differentiated synovial sarcoma.

Epidemiology and Demographics

• The incidence of PNETs is from birth to 20 years of age approximately 0.29 per 100,000.
• The prevalence of primitive neuroectodermal tumors remains unknown.
• PNETs are more common among children.
• PNETs are more prevalent in men than women.
• PNETs are more prevalent in Hispanic and white races.

Risk Factors

• The most potent risk factor in the development of PNET is prenatal exposure to alcohol prenatal.
• Children who had lived in farms for at least 1 year showed an increased risk for PNET.
• Certain syndromes seem to play the role of a risk factor for PNETs including the following:
  • Gorlin syndrome
  • Turcot syndrome
  • Coffin-Siris syndrome
  • Cowden syndrome
  • Gardner syndrome
  • Li-Fraumeni syndrome
  • Rubinstein-Taybi syndrome

Natural History, Complications and Prognosis

• If left untreated, patients with primitive neuroectodermal tumors may develop metastases.
• Common complications of the primitive neuroectodermal tumor include increased intracranial pressure, cranial nerve palsy, and seizures.
• Prognosis is generally poor, and the 5-year survival rate of patients with PNET less than 35% in adults and 64% in children.
• Prognosis is better in adult patients.
• Features associated with favorable prognosis include early diagnosis, combination treatment approach including tumor resection, chemotherapy and radiotherapy, intratumoral calcification, Ki-67 <30%, elevated LDH, tumor volume >100 cc, and axial location.

Diagnosis

History and Symptoms

• The majority of patients with primitive neuroectodermal tumors remain asymptomatic for years.
• Clinical presentation of primitive neuroectodermal tumors is often non-specific and depend on the site of the tumor.
• Patients with PNETs may present with only constitutional symptoms such as fever, severe pain, and paresthesia.
• Other symptoms of primitive neuroectodermal tumor may include the following:
  • Morning headache
  • Restlessness
  • Recurrent vomiting
  • Diplopia
  • Frequent falls
  • Positional dizziness
  • Forgetfulness
  • Progressive visual disturbances

Physical Examination

• Physical examination may be remarkable for papilledema, strabismus, nystagmus, imbalance, motor weakness, facial sensory loss, third, fourth, and sixth cranial nerve palsies, hemiplegia, hepatosplenomegaly, and adenopathy.

Laboratory Findings

• Laboratory findings consistent with the diagnosis of primitive neuroectodermal tumor include elevated erythrocyte sedimentation rate, positive C-reactive protein, anemia, leukocytosis, thrombocytosis, hypoalbuminemia, increased LDH levels.
• Neuroblastoma may be associated with an elevated level of urinary catecholamines.

Electrocardiogram

• There are no ECG findings associated with primitive neuroectodermal tumors.

X-ray

• There are no x-ray findings associated with primitive neuroectodermal tumors.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with primitive neuroectodermal tumors.

CT

• On CT, findings associated with the diagnosis of primitive neuroectodermal tumor, may include a large irregular mass with heterogeneous contrast enhancement. Cystic components and calcification are also common.

Axial T2 image of PNET, Case courtesy of Dr Prashant Mudgal, Radiopaedia.org, rID: 32696

MRI

• MRI is the imaging modality of choice for primitive neuroectodermal tumors.
• On MRI, findings of the primitive neuroectodermal tumor may include highly variable and can be hypo-intense to isointense, but usually, hypo-intense on T1-weighted images and high signal solid components on T2-weighted images.

Other Imaging Findings

• There are no other imaging findings associated with primitive neuroectodermal tumors.

Other Diagnostic Studies

• There are no other diagnostic studies associated with primitive neuroectodermal tumors.

Treatment

Medical Therapy

• There is no treatment for PNET.
• Chemotherapy is controversial in the treatment of PNET.
• For the management of peripheral form of PNET, systemic chemotherapy has been associated with a better prognosis and is generally recommended.

Surgery

• The feasibility of surgery depends on the site of the tumor, at diagnosis. Maximum resection must be performed.

Primary Prevention

• There are no primary preventive measures available for primitive neuroectodermal tumors.

Secondary Prevention

• There are no secondary preventive measures available for primitive neuroectodermal tumors.