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 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 is 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 believed 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, the 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.
• In 1983, Rorke used the term PNET to describe all undifferentiated CNS tumors with neuroepithelial origin, irrespective of their site.

Classification

• Primitive neuroectodermal tumor may be classified based on the embryonic derivatives according to World Health Organization into 2 subtypes:

• central primitive neuroectodermal tumors(PNETs) which can include CNS neuroblastoma, CNS ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma.
• 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), and pelvis.

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.
• On microscopy histopathological analysis, small round blue cells, fine chromatin, eosinophilic cytoplasm,homer-Wright rosettes, and high mitotic figures.
• On microscopic histopathological analysis, characteristic findings of the primitive neuroectodermal tumor, include small blue cell tumorRound hyperchromatic cells, abundant mitotic figures, Homer-Wright rosettes, in which tumor cells surround neutrophils, fibrosis, and short and round or spindle-shaped nuclei.
• Immunohistochemical analysis can reveal differentiation toward different directions such as glial, neuronal and ependymal .
• Immunohistochemical analysis can also be positive for CD99, CD56, Neuron-specific enolase (NSE), S-100 protein, synaptophysin, and chromogranin A.

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

Causes

• The t (11;22)(q24;q12) translocation seen in most of the 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 an increase in intracranial pressure, such as astrocytoma, ependymoma, oligodendroglioma, intracranial teratoma, meningitis, encephalitis, and other brain tumors.

Epidemiology and Demographics

• The prevalence of primitive neuroectodermal tumors 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.
• 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 adult brain tumors.
• PNETs have a slight tendency toward affecting men compared to women .
• 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 an increased risk for PNET.
• Certain syndromes seem to play as risk factors for PNETs including Gorlin syndrome, Turcot syndrome, Coffin-Siris syndrome, Cowden syndrome, Gardner syndrome, Li-Fraumeni syndrome, and Rubinstein-Taybi syndrome.

Natural History, Complications and Prognosis

• The majority of patients with primitive neuroectodermal tumors remain asymptomatic for years.
• Early clinical features are often unspecific.
• If left untreated, patients with primitive neuroectodermal tumors may progress to develop metastases.
• Common complications of the primitive neuroectodermal tumor, include increased intracranial pressure, cranial nerve palsy, and 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 a better prognosis.
• Features associated with good prognosis include early diagnosis, combinatorial treatment approach including tumor resection, chemotherapy and radiotherapy, intratumoral calcification, Ki-67 <30%, high LDH, tumor volume >100 cc, and axial location.

Diagnosis

History and 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 morning headache, restlessness, recurrent vomiting, diplopia, frequent falls, positional dizziness, forgetfulness, progressive impaired vision, Constitutional symptoms such as fever, severe pain, and paresthesia.

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 associated with the diagnosis of primitive neuroectodermal tumor may include
• elevated erythrocyte sedimentation rate, positive C-reactive protein, anemia, leukocytosis, thrombocytosis, hypoalbuminemia, increased LDH levels.

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

• There are no CT scan findings associated with primitive neuroectodermal tumors.

MRI

• MRI is the imaging modality of choice for primitive neuroectodermal tumors.
• On CT, findings of the 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 heterogeneous contrast enhancement

• 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 generally high signal solid components on T2-weighted images.

• MRI with contrast shows acid enhancement, cystic components, necrosis, and Calcification
• Tumor has well-defined borders without peripheral edema
• T1 C+ (Gd): shows markedly heterogeneous 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-acetyl aspartate (NAA), elevated taurine (Tau) peak (relatively specific for PNET).

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

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 consensus in the treatment of PNET.
• Chemotherapy is controversial in the treatment of PNET.
• Temozolomide can be added to conventional treatment of excision and radiotherapy.
• 7 to 8 weeks of radiotherapy at a dose of 50-55 Gy is recommended .

Surgery

• Based on the site of the tumor, 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.