Primitive neuroectodermal tumor

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

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 neural crest tumor. PNET arises from the neuroectoderm, which 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 are more commonly was described in 1973 by Hart and Earle . In fact, PNETs are members of the Ewing tumor family. These tumors have small round cells, are belived to originate from postganglionic parasympathetic primordial cells and have mutations of the EWS gene. Due to their origin, PNETs can be found at any site within the parasympathetic system. Apart from Ewing Sarcoma (ES) and PNET, this family of tumors includes other tumors such as Askin's tumor (a malignant small-cell tumor in the chest) and paravertebral small-cell tumors. PNETs are divided into peripheral and central based on their presentation site. Central PNETs are more commonly seen among children and young adults and account for approximately 1% of PNETs. Peripheral PNETs mostly occur in bones and surrounding tissues. PNETs are more commonly seen among children and young adults . The median age at diagnosis is 25 years of age. PNETs are highly malignant and their prognosis is generally poor, however prognosis is more favorable for adult patients with PNET. The 5-survival rate of patients with PNET is less than 35%. The disease affects both men and women, however there is a slight tendency toward affecting males in the cases of peripheral PNET.

Historical Perspective

• Primitive neuroectodermal tumor was first discovered by James Ewing, an American pathologist, in 1921.
• The term PNET was first coined in 1973 by Hart and Earle, describing PNETs in children .
• In 1983, Rorke used the term PNET to describe all undifferentiated CNS tumors with neuroepithelial origin, irrespective of their site .

Classification

• Previously, PNETs were classified as embryonic tumors of the CNS.
• Primitive neuroectodermal tumor may be classified according to World Health Organization into 3 subtypes:

• Central primitive neuroectodermal tumors (PNETs), which can include:
  • supratentorial tumors
  • infratentorial tumors (medulloblastoma) PNET of the brain stem and spinal cord were previously categorized as different groups, however, they are now considered as CNS PNETs.
• Neuroblastomas, which can be both central and peripheral, mostly arising from adrenal glands.
• Peripheral primitive neuroectodermal tumors (pPNETs), with most of the tumors arising in:
  • bone and surrounding tissues, especially of the limbs
  • paravertebral regions
  • chest (Askin's tumor)
  • pelvis Peripheral PNETs and central PNETs are two completely different types of tumors as they are different immunohistochemically and in their background and genetics.

Pathophysiology

• The t(11;22)(q24;q12) translocation seen in most of the Ewing sarcoma and PNET.
• This translocation fuses the EWS gene on chromosome 22 with the FLI1 gene on chromosome 11. The resulting EWS-FLI1gene is functional and leads to production of a new functional protein.
• This new protein increases the expression of some oncogenic genes.
• These proteins lead to undifferentiated proliferation of neuroepithelial cells.
• PNET is composed of primitive undifferentiated neuroepithelial cells.

Causes

• The t(11;22)(q24;q12) translocation seen in most of PNET cases seems to play a causative role.

Differentiating Primitive Neuroectodermal Tumor from Other Diseases

• Primitive neuroectodermal tumor must be differentiated from other diseases that cause seizures, or increase on intracranial pressure, such as:

• Astrocytoma
• Ependymoma
• Oligodendroglioma
• Intracranial teratoma
• Other brain tumors
• Meningitis
• Encephalitis

Epidemiology and Demographics

• The prevalence of primitive neuroectodermal tumor remains unknown.
• The annual incidence of PNETs from birth to 20 years of age is 2.9 per 1,000,000.
• Primitive neuroectodermal tumor account for 4-17% of all soft tissue pediatric tumors.

Age

• The median age at diagnosis depends on the type of PNET and their location.
• PNETs are more common among children and account for 2.5% of brain tumors in children .
• Adults are much less affected by PNETs and these tumors account for 0.46% of adulthood brain tumors.

Gender

• PNETs have a slight tendency toward affecting men compared to women .

Race

• PNETs are extremely rare in African and Asian individuals.
• PNETs usually affect Hispanic and white individuals.
• Peripheral PNET, has a tendency toward affecting Caucasians .

Risk Factors

• Prenatal exposure to alcohol seems to be a risk factor for developing PNET .
• Children who had lived in farms for at least 1 year showed increased risk for PNET .
• Certain syndromes seem to play as risk factors for PNETs:

• Gorlin syndrome
• Turcot syndrome
• Coffin-Siris syndrome
• Cowden syndrome
• Gardner syndrome
• Li-Fraumeni syndrome
• Rubinstein-Taybi syndrome

Natural History, Complications and Prognosis

• The majority of patients with primitive neuroectodermal tumor remain asymptomatic for years.
• Early clinical features are often unspecific.
• If left untreated, patients with primitive neuroectodermal tumor may progress to develop metastases.
• Common complications of primitive neuroectodermal tumor, include:

• Increased intracranial pressure
• Cranial nerve palsy
• Seizures

• Prognosis is similar for peripheral PNETs and central PNETs.
• Prognosis is generally poor, and the 5-survival rate of patients with PNET less than 35% in adults and 64% in children.
• Prognosis is more favorable for adult patients.
• Tumors expressing CD99 are less aggressive after surgical resection and have better prognosis.
• Features associated with good prognosis include:
  • Early diagnosis
  • Combinatorial treatmrnt approach including tumor resection, chemotherapy and radiotherapy
  • intratumoral calcification
  • Ki-67 <30%
  • High LDH
  • Tumor volume >100 cc
  • Axial location

Diagnosis

Symptoms

• Clinical presentation of primitive neuroectodermal tumors is often non-specific and depend on the site of the tumor.
• Symptoms of primitive neuroectodermal tumor may include the following:

• Morning headache
• Restlessness
• Recurrent vomiting
• Diplopia
• Frequent falls
• Positional dizziness
• Forgetfulness
• Progressive impaired vision
• Constitutional symptoms such as fever, severe pain,... .
• Paresthesia

Physical Examination

• Physical examination may be remarkable for:

• Seizures
• Papilledema
• Strabismus
• Nystagmus
• Ataxia
• Motor weakness
• Facial sensory loss
• Third, fourth, and sixth cranial nerve palsies
• Hemiplegia
• Hepatosplenomegaly
• Adenopathy

Laboratory Findings

• Elevated erythrocyte sedimentation rate
• Positive C-reactive protein
• Anemia
• Leukocytosis
• Thrombocytosis
• Hypoalbuminemia
• Increased LDH levels

Microscopic Histopathology

• Microscopic features of PNETs show a proliferation as the mechanism of growth rather than infiltration.
• On microscopic histopathological analysis, characteristic findings of primitive neuroectodermal tumor, include:

• Small blue cell tumor

  

  H&E staining of PNET. Courtesy of image: Wikipedia

  Round hyperchromatic cells
• Abundant mitotic figures
• Homer-Wright rosettes, in which tumor cells surround neutrophils.
• Fibrosis
• short and round or spindle-shaped nuclei Immunohistochemical analysis can reveal differentiation toward different directions such as glial, neuronal and ependymal .

Immunohistochemicsl analysis can be positive for:

• CD99
• CD56
• Neuron-specific enolase (NSE)
• S-100 protein
• Synaptophysin
• Chromogranin A

Imaging Findings

• MRI is the imaging modality of choice for primitive neuroectodermal tumor.
• On CT, findings of primitive neuroectodermal tumor, may include:

• Often seen as a large irregular mass
• Typically iso to hyper-attenuating on non contrast imaging
• Cystic components are common (65%)
• Calcification can be common (70% )
• Shows heterogenous contrast enhancement

• On MRI, findings of primitive neuroectodermal tumor, may include:

• T1: highly variable and can be hypo-intense to isointense, but usually hypo-intense
• T2: generally high signal solid components
• MRI with contrast shows acid enhancement
• Cystic components and necrosis are common
• Calcification and hemorrhage is common within the tumors
• Tumor has well-defined borders without peripheral edema
• T1 C+ (Gd): shows markedly heterogenous enhancement and leptomeningeal seeding is common
• DWI: often shows restricted diffusion and solid composition in addition to enhancement which shows high vascularization of the tumor.
• MR spectroscopy: elevated choline, decreased N-acetylaspartate (NAA), elevated taurine (Tau) peak (relatively specific for PNET).

In cases of peripheral PNET, whole body radioisotope scan can reveal the site of the tumor and possible metastases.

Treatment

Medical Therapy

• There is no consensus in treatment of PNET.
• Chemotherapy is controversial in treatment of PNET.
• Temozolomide can be added to conventional treatment of excision and radiotherapy.

Surgery

• Based on the site of the tumor, maximum resection must be performed.

Radiotherapy

• 7 to 8 weeks of radiotherapy at a dose of 50-55 Gy is recommended .

Prevention

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