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{{SK}} Primitive neuroectodermal tumors; PNET; CNS PNET;  Askin tumor; Peripheral neuroepithelioma; Ependymoblastoma
{{SK}} Primitive neuroectodermal tumors; PNET; CNS PNET;  Askin tumor; Peripheral neuroepithelioma; Ependymoblastoma
==Overview==
==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 [[classification|classified]] into 3 subtypes. [[Histopathological|Histopathologically]], PNETs should be [[Differentiate|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]], [[ataxia|imbalance]], motor [[weakness]], facial [[sensory loss]], third, fourth, and sixth [[cranial nerve palsies]], [[hemiplegia]], [[hepatosplenomegaly]], and [[lymphadenopathy|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.
'''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 [[Mutation|mutations]] of the EWS gene. Due to their origin, PNETs can be found at any site within the [[Parasympathetic nervous system|parasympathetic system]]. Apart from [[Ewing Sarcoma|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==
==Historical Perspective==
*Primitive neuroectodermal tumor was first discovered by James Ewing, an American [[pathologist]], in 1921.<ref name="pmid31417299">{{cite journal| author=Yagnik VD, Dawka S| title=Extraskeletal Ewing's sarcoma/peripheral primitive neuroectodermal tumor of the small bowel presenting with gastrointestinal perforation. | journal=Clin Exp Gastroenterol | year= 2019 | volume= 12 | issue= | pages= 279-285 | pmid=31417299 | doi=10.2147/CEG.S203697 | pmc=6600760 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31417299  }} </ref>
*Primitive neuroectodermal tumor was first discovered by James Ewing, an American [[pathologist]], in 1921.<ref name="YagnikDawka2019">{{cite journal|last1=Yagnik|first1=Vipul D|last2=Dawka|first2=Sushil|title=<p>Extraskeletal Ewing’s sarcoma/peripheral primitive neuroectodermal tumor of the small bowel presenting with gastrointestinal perforation</p>|journal=Clinical and Experimental Gastroenterology|volume=Volume 12|year=2019|pages=279–285|issn=1178-7023|doi=10.2147/CEG.S203697}}</ref>
*In 1983, Rorke used the term PNET to describe all [[undifferentiated]] [[CNS tumor|CNS tumors]] with [[Neuroepithelial cell|neuroepithelial]] [[origin]], irrespective of their site <ref>{{Cite journal|last=Rorke LB.|first=|date=1983|title=The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors.|url=https://www.ncbi.nlm.nih.gov/pubmed/6296325|journal=J Neuropathol Exp Neuro|volume=|pages=|via=}}</ref>.
*In 1983 the term PNET was first used by Rorke to describe all [[undifferentiated]] [[CNS tumor|CNS tumors]] with [[Neuroepithelial cell|neuroepithelial]] [[origin]], irrespective of their site.<ref>{{Cite journal|last=Rorke LB.|first=|date=1983|title=The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors.|url=https://www.ncbi.nlm.nih.gov/pubmed/6296325|journal=J Neuropathol Exp Neuro|volume=|pages=|via=}}</ref>
 
==Classification==
==Classification==
*Previously, PNETs were classified as embryonic tumors of the [[CNS]].
*Primitive neuroectodermal tumor may be [[classification|classified]] into 3 sub-types:<ref name="BatsakisMacKay2016">{{cite journal|last1=Batsakis|first1=John G.|last2=MacKay|first2=Bruce|last3=El-Naggar|first3=Adel K.|title=Ewing's Sarcoma and Peripheral Primitive Neuroectodermal Tumor: An Interim Report|journal=Annals of Otology, Rhinology & Laryngology|volume=105|issue=10|year=2016|pages=838–843|issn=0003-4894|doi=10.1177/000348949610501014}}</ref>
*Primitive neuroectodermal tumor may be classified according to World Health Organization into 3 subtypes:<ref name="PNET">PNET. Wikipedia. https://en.wikipedia.org/wiki/Primitive_neuroectodermal_tumor Acceded on May 23, 2016</ref>
**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 [[classification|classified]] into [[Ewing sarcoma]], [[malignant]] peripheral primitive neuroectodermal tumors, Askin [[tumor]], and less common [[tumors]] (eg, [[Neuroectodermal melanolysosomal disease|neuroectodermal]] [[tumor]], ectomesenchymoma, peripheral [[medulloepithelioma]]).<ref name="CastroParwani2012">{{cite journal|last1=Castro|first1=E. C.|last2=Parwani|first2=A. V.|title=Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: Two Unusual Presentations of a Rare Tumor|journal=Case Reports in Medicine|volume=2012|year=2012|pages=1–7|issn=1687-9627|doi=10.1155/2012/190581}}</ref><ref name="pmid30005673">{{cite journal |vauthors=Triarico S, Attinà G, Maurizi P, Mastrangelo S, Nanni L, Briganti V, Meacci E, Margaritora S, Balducci M, Ruggiero A |title=Multimodal treatment of pediatric patients with Askin's tumors: our experience |journal=World J Surg Oncol |volume=16 |issue=1 |pages=140 |date=July 2018 |pmid=30005673 |pmc=6044084 |doi=10.1186/s12957-018-1434-2 |url=}}</ref>
:*Central primitive neuroectodermal tumors(PNETs), which can include:
**[[Neuroblastoma]] which is derived from the [[autonomic nervous system]].
:**[[supratentorial]] tumors
:**[[Infratentorial PNET|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==
==Pathophysiology==
*The t(11;22)(q24;q12) translocation seen in most of the Ewing sarcoma and PNET.  
*The [[pathogenesis]] of peripheral primitive neuroectodermal tumor is characterized by the [[chromosomal translocation]] t(11;22)(q24q12).<ref name="pmid1283315">{{cite journal| author=Zucman J, Delattre O, Desmaze C, Plougastel B, Joubert I, Melot T et al.| title=Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints. | journal=Genes Chromosomes Cancer | year= 1992 | volume= 5 | issue= 4 | pages= 271-7 | pmid=1283315 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1283315  }} </ref><ref name="pmid1522903">{{cite journal| author=Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M et al.| title=Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. | journal=Nature | year= 1992 | volume= 359 | issue= 6391 | pages= 162-5 | pmid=1522903 | doi=10.1038/359162a0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1522903  }} </ref>
*This [[Chromosomal translocation|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 [[Chromosomal translocation|translocation]] fuses the [[EWSR1 gene|EWS]] [[gene]] on [[chromosome 22]] with the [[FLI1]] [[gene]] on [[chromosome 11]].
*This new protein increases the expression of some [[oncogenic]] genes.  
*The EWS-FLI1 [[gene]] has been associated with the development of PNET involving the synthesis of [[adrenal]] pathway.
*These proteins lead to undifferentiated [[Cell growth|proliferation]] of neuroepithelial cells.
*On [[gross]] [[pathology]], white, [[hemorrhagic]] and [[necrotic]] [[mass]] are characteristic of PNET.<ref name="pmid26793768">{{cite journal| author=Novo J, Bitterman P, Guirguis A| title=Central-type primitive neuroectodermal tumor of the uterus: Case report of remission of stage IV disease using adjuvant cisplatin/etoposide/bevacizumab chemotherapy and review of the literature. | journal=Gynecol Oncol Rep | year= 2015 | volume= 14 | issue=  | pages= 26-30 | pmid=26793768 | doi=10.1016/j.gore.2015.09.002 | pmc=4688884 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26793768  }} </ref>
*PNET is composed of primitive undifferentiated neuroepithelial cells.<ref name="PNET">PNET. Wikipedia. https://en.wikipedia.org/wiki/Primitive_neuroectodermal_tumor Acceded on May 23, 2016</ref>


==Causes==
{| align="right"
* The  t(11;22)(q24;q12) translocation seen in most of PNET cases seems to play a causative role.
|[[File:PNET Histopathology HE 200x.jpg|thumb|right|200px|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 cell|tumor cells]] surround [[neutrophils]], [[fibrosis]], and short and round or spindle-shaped [[nuclei]].<ref name="pmid7803540">{{cite journal| author=Jürgens HF| title=Ewing's sarcoma and peripheral primitive neuroectodermal tumor. | journal=Curr Opin Oncol | year= 1994 | volume= 6 | issue= 4 | pages= 391-6 | pmid=7803540 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7803540  }} </ref><ref name="pmid10623711">{{cite journal| author=de Alava E, Gerald WL| title=Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. | journal=J Clin Oncol | year= 2000 | volume= 18 | issue= 1 | pages= 204-13 | pmid=10623711 | doi=10.1200/JCO.2000.18.1.204 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10623711  }} </ref>
*[[Immunohistochemical]] analysis can also be positive for [[CD99]], [[CD56]], [[Neuron-specific enolase]] (NSE), [[S-100 protein]], [[synaptophysin]], and [[chromogranin A]].<ref name="AlonsoYi2017">{{cite journal|last1=Alonso|first1=Marta M.|last2=Yi|first2=Xiaoping|last3=Liu|first3=Wenguang|last4=Zhang|first4=Youming|last5=Xiao|first5=Desheng|last6=Yin|first6=Hongling|last7=Long|first7=Xueying|last8=Li|first8=Li|last9=Zai|first9=Hongyan|last10=Chen|first10=Minfeng|last11=Li|first11=Wenzheng|last12=Sun|first12=Lunquan|title=Radiological features of primitive neuroectodermal tumors in intra-abdominal and retroperitoneal regions: A series of 18 cases|journal=PLOS ONE|volume=12|issue=3|year=2017|pages=e0173536|issn=1932-6203|doi=10.1371/journal.pone.0173536}}</ref>
==Differentiating Primitive Neuroectodermal Tumor from Other Diseases==
==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:<ref name="PNET">PNET. Wikipedia. https://en.wikipedia.org/wiki/Primitive_neuroectodermal_tumor Acceded on May 23, 2016</ref>
*Primitive neuroectodermal tumor must be [[Differentiate|differentiated]] from other [[diseases]] that cause [[seizures]] or an [[Increased intracranial pressure|increase in intracranial pressure]], such as [[astrocytoma]], [[ependymoma]], [[oligodendroglioma]], intracranial [[teratoma]], [[meningitis]], [[encephalitis]], and other [[brain]] [[tumors]].
 
*[[Histopathological|Histopathologically]], primitive neuroectodermal tumors should be [[Differentiate|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]].<ref name="pmid1848471">{{cite journal |vauthors=Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H, Salzer-Kuntschik M |title=MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration |journal=Cancer |volume=67 |issue=7 |pages=1886–93 |date=April 1991 |pmid=1848471 |doi=10.1002/1097-0142(19910401)67:7<1886::aid-cncr2820670712>3.0.co;2-u |url=}}</ref>
:*Astrocytoma
:*Ependymoma
:*Oligodendroglioma
:*Intracranial teratoma
:*Other brain tumors
:*Meningitis
:*Encephalitis
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* The prevalence of primitive neuroectodermal tumor remains unknown.
*The incidence of PNETs is from birth to 20 years of age approximately 0.29 per 100,000.<ref name="ViseeSoltner2005">{{cite journal|last1=Visee|first1=S|last2=Soltner|first2=C|last3=Rialland|first3=X|last4=Machet|first4=M C|last5=Loussouarn|first5=D|last6=Milinkevitch|first6=S|last7=Pasco-Papon|first7=A|last8=Mercier|first8=P|last9=Rousselet|first9=M C|title=Supratentorial primitive neuroectodermal tumours of the brain: multidirectional differentiation does not influence prognosis. A clinicopathological report of 18 patients|journal=Histopathology|volume=46|issue=4|year=2005|pages=403–412|issn=0309-0167|doi=10.1111/j.1365-2559.2005.02101.x}}</ref>
* The annual incidence of PNETs from birth to 20 years of age is 2.9 per 1,000,000.
*The [[prevalence]] of primitive neuroectodermal tumors remains unknown.
* Primitive neuroectodermal tumor account for 4-17% of all soft tissue pediatric tumors.<ref name="PNET">PNET. Wikipedia. https://en.wikipedia.org/wiki/Primitive_neuroectodermal_tumor Acceded on May 23, 2016</ref>
*PNETs are more common among children.
*PNETs are more prevalent in men than women.<ref>{{Cite journal|last=Ohba S, Yoshida K, Hirose Y, Ikeda E, Kawase T.|first=|date=2008|title=A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature.|url=|journal=J Neurooncol|volume=|pages=|via=}}</ref>
===Age===
*PNETs are more prevalent in Hispanic and white races.  
*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 <ref>{{Cite journal|last=Visee S, Soltner C, Rialland X, Machet MC, Loussouarn D, Milinkevitch S, et al.|first=|date=2005|title=Supratentorial primitive neuroectodermal
tumors of the brain: multidirectional differentiation
does not influence prognosis. A clinicopathological report of 18 patients.|url=|journal=Histopathology|volume=|pages=|via=}}</ref>.
*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 <ref>{{Cite journal|last=Ohba S, Yoshida K, Hirose Y, Ikeda E, Kawase T.|first=|date=2008|title=A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature.|url=|journal=J Neurooncol|volume=|pages=|via=}}</ref>.
===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 <ref name=":1" />.
==Risk Factors==
==Risk Factors==
*Prenatal exposure to alcohol seems to be a risk factor for developing PNET <ref name=":2">{{Cite journal|last=G R Bunin, J D Buckley, C P Boesel, L B Rorke and A T Meadows|first=|date=1994|title=Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group.|url=http://cebp.aacrjournals.org/content/3/3/197.full-text.pdf|journal=Cancer Epidemiol Biomarkers Prev.|volume=|pages=|via=}}</ref>.
*The most potent risk factor in the development of PNET is prenatal exposure to [[alcohol]] prenatal.<ref name=":2">{{Cite journal|last=G R Bunin, J D Buckley, C P Boesel, L B Rorke and A T Meadows|first=|date=1994|title=Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group.|url=http://cebp.aacrjournals.org/content/3/3/197.full-text.pdf|journal=Cancer Epidemiol Biomarkers Prev.|volume=|pages=|via=}}</ref>
*Children who had lived in farms for at least 1 year showed increased risk for PNET <ref name=":2" />.
*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:
*Certain [[syndromes]] seem to play the role of a [[risk factor]] for PNETs including the following:  
:* [[Gorlin syndrome]]
**[[Gorlin syndrome]]  
:* [[Turcot syndrome]]
**[[Turcot syndrome]]
:* [[Coffin-Siris syndrome]]
**[[Coffin-Siris syndrome]]  
:* [[Cowden syndrome]]
**[[Cowden syndrome]]  
:* [[Gardner syndrome]]
**[[Gardner syndrome]]
:* [[Li-Fraumeni syndrome]]
**[[Li-Fraumeni syndrome]]
:* [[Rubinstein-Taybi syndrome]]
**[[Rubinstein-Taybi syndrome]]


== Natural History, Complications and Prognosis==
== 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 tumors may develop [[metastases]].<ref>{{Cite journal|last=Smoll NR.|first=|date=2012|title=Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs).|url=|journal=Cancer|volume=|pages=|via=}}</ref>
*If left untreated, patients with primitive neuroectodermal tumor may progress to develop metastases.
*Common [[complications]] of the primitive neuroectodermal tumor include [[increased intracranial pressure]], [[cranial nerve palsy]], and [[seizures]].
*Common complications of primitive neuroectodermal tumor, include:
*[[Prognosis]] is generally poor, and the 5-year [[survival rate]] of [[patients]] with PNET less than 35% in adults and 64% in [[children]].
:*Increased intracranial pressure
*[[Prognosis]] is better in adult [[Patient|patients]].
:*Cranial nerve palsy
*Features associated with favorable [[prognosis]] include early [[diagnosis]], combination treatment approach including [[tumor]] resection, [[chemotherapy]] and [[radiotherapy]], intratumoral [[calcification]], [[Ki-67 (Biology)|Ki-67]] <30%, elevated [[LDH]], [[tumor]] volume >100 [[Mili litr|cc]], and [[axial]] location.
:*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<ref>{{Cite journal|last=Smoll NR.|first=|date=2012|title=Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs).|url=|journal=Cancer|volume=|pages=|via=}}</ref>.
*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 (Biology)|Ki-67]] <30%
**High LDH
**Tumor volume >100 cc
**Axial location
*
== Diagnosis ==
== Diagnosis ==
=== Symptoms ===
=== History and Symptoms ===
*Clinical presentation of primitive neuroectodermal tumors is often non-specific and depend on the site of the tumor.  
* The majority of [[patients]] with primitive neuroectodermal tumors remain [[asymptomatic]] for years.<ref name="pmid2776115">{{cite journal |vauthors=Rud NP, Reiman HM, Pritchard DJ, Frassica FJ, Smithson WA |title=Extraosseous Ewing's sarcoma. A study of 42 cases |journal=Cancer |volume=64 |issue=7 |pages=1548–53 |date=October 1989 |pmid=2776115 |doi=10.1002/1097-0142(19891001)64:7<1548::aid-cncr2820640733>3.0.co;2-w |url=}}</ref><ref name="pmid20959975">{{cite journal |vauthors=Li X, Zhang W, Song T, Sun C, Shen Y |title=Primitive neuroectodermal tumor arising in the abdominopelvic region: CT features and pathology characteristics |journal=Abdom Imaging |volume=36 |issue=5 |pages=590–5 |date=October 2011 |pmid=20959975 |doi=10.1007/s00261-010-9655-z |url=}}</ref>
*Symptoms of primitive neuroectodermal tumor may include the following:
*[[Clinical]] presentation of primitive neuroectodermal tumors is often non-specific and depend on the site of the [[tumor]].
:* [[Morning headache]]
*Patients with PNETs may present with only constitutional [[symptoms]] such as [[fever]], severe [[pain]], and [[paresthesia]].
:* [[Restlessness]]
*Other [[Symptom|symptoms]] of primitive neuroectodermal tumor may include the following:
:* Recurrent [[vomiting]]
**[[Morning headache]]
:* [[Diplopia]]
**[[Restlessness]]
:* Frequent falls
**Recurrent [[vomiting]]
:* Positional [[dizziness]]
**[[Diplopia]]
:* [[Forgetfulness]]  
**Frequent falls  
:* Progressive impaired vision
**Positional [[dizziness]]
:* [https://en.wikipedia.org/wiki/Constitutional_symptoms Constitutional symptoms] such as fever, severe pain,... .
**[[Forgetfulness]]
:* [[Paresthesia]]
**Progressive [[visual]] disturbances
:* 
 
=== Physical Examination ===
=== Physical Examination ===
*Physical examination may be remarkable for:
*[[Physical examination]] may be remarkable for [[papilledema]], [[strabismus]], [[nystagmus]], [[ataxia|imbalance]], motor [[weakness]], facial [[sensory loss]], third, fourth, and sixth [[cranial nerve palsies]], [[hemiplegia]], [[hepatosplenomegaly]], and [[lymphadenopathy|adenopathy]].<ref name="pmid2776115">{{cite journal |vauthors=Rud NP, Reiman HM, Pritchard DJ, Frassica FJ, Smithson WA |title=Extraosseous Ewing's sarcoma. A study of 42 cases |journal=Cancer |volume=64 |issue=7 |pages=1548–53 |date=October 1989 |pmid=2776115 |doi=10.1002/1097-0142(19891001)64:7<1548::aid-cncr2820640733>3.0.co;2-w |url=}}</ref>
:* Seizures
:* [[Papilledema]]
:* [[Strabismus]]
:* [[Nystagmus]]
:* [[Ataxia]]
:* Motor [[weakness]]
:* Facial [[sensory loss]]
:* Third, fourth, and sixth [[cranial nerve palsies]]
:* [[Hemiplegia]]  
:* [[Hepatosplenomegaly]]
:* [[Lymphadenopathy|Adenopathy]]
:* 
=== Laboratory Findings ===
=== Laboratory Findings ===
*Elevated [[erythrocyte sedimentation rate]]  
*[[Laboratory]] findings consistent with the [[diagnosis]] of primitive neuroectodermal tumor include elevated [[erythrocyte sedimentation rate]], positive [[C-reactive protein]], [[anemia]], [[leukocytosis]], [[thrombocytosis]], [[hypoalbuminemia]], increased [[Lactate dehydrogenase|LDH]] levels.<ref name="pmid3992134">{{cite journal |vauthors=Bacci G, Capanna R, Orlandi M, Mancini I, Bettelli G, Dallari D, Campanacci M |title=Prognostic significance of serum lactic acid dehydrogenase in Ewing's tumor of bone |journal=Ric Clin Lab |volume=15 |issue=1 |pages=89–96 |date=1985 |pmid=3992134 |doi= |url=}}</ref>
*Positive [[C-reactive protein]]  
*[[Neuroblastoma]] may be associated with an elevated level of [[urinary]] [[catecholamines]].<ref name="pmid16732582">{{cite journal |vauthors=Strenger V, Kerbl R, Dornbusch HJ, Ladenstein R, Ambros PF, Ambros IM, Urban C |title=Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients |journal=Pediatr Blood Cancer |volume=48 |issue=5 |pages=504–9 |date=May 2007 |pmid=16732582 |doi=10.1002/pbc.20888 |url=}}</ref>
*[[Anemia]]  
*[[Leukocytosis]]  
*[[Thrombocytosis]]  
*[[Hypoalbuminemia]]  
*Increased [[Lactate dehydrogenase|LDH]] levels  


=== Microscopic Histopathology ===
=== Electrocardiogram ===
*Microscopic features of PNETs show a proliferation as the mechanism of growth rather than infiltration.
*There are no [[ECG]] findings associated with primitive neuroectodermal tumors.
*On microscopic histopathological analysis,  characteristic findings of primitive neuroectodermal tumor, include:<ref name="PNET" />
=== X-ray ===
 
*There are no [[x-ray]] findings associated with primitive neuroectodermal tumors.
:*Small blue cell tumor[[File:PNET Histopathology HE 200x.jpg|thumb|H&E staining of PNET. Courtesy of image: [https://en.wikipedia.org/wiki/Primitive_neuroectodermal_tumor Wikipedia]]]Round hyperchromatic cells
=== Echocardiography or Ultrasound ===
:*Abundant mitotic figures
*There are no [[echocardiography]]/[[ultrasound]] findings associated with primitive neuroectodermal tumors.
:*Homer-Wright rosettes, in which tumor cells surround neutrophils.  
=== CT ===
:*Fibrosis
*On [[Computed tomography|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.<ref name="pmid26847997">{{cite journal |vauthors=Xiao H, Bao F, Tan H, Wang B, Liu W, Gao J, Gao X |title=CT and clinical findings of peripheral primitive neuroectodermal tumour in children |journal=Br J Radiol |volume=89 |issue=1060 |pages=20140450 |date=2016 |pmid=26847997 |pmc=4846188 |doi=10.1259/bjr.20140450 |url=}}</ref>
:*short and round or spindle-shaped nuclei Immunohistochemical analysis can reveal differentiation toward different directions such as [[Glial tumor|glial]], neuronal and ependymal<ref>{{Cite journal|last=Pigott TJ, Punt JA, Lowe JS, Henderson MJ, Beck A, Gray T|first=|date=1990|title=The clinical, radiological and histopathological features of cerebral primitive neuroectodermal tumours.|url=|journal=Br J Neurosurg.|volume=|pages=|via=}}</ref> .
{| align="right"
:Immunohistochemicsl analysis can be positive for<ref name=":3" />:
|[[File:Primitive-neuroectodermal-tumour-of-the-cns-1.jpg|thumb|right|200px|Axial T2 image of PNET, Case courtesy of Dr Prashant  Mudgal, Radiopaedia.org, rID: 32696]]
:* CD99
|}
:* CD56
=== MRI ===
:* Neuron-specific enolase (NSE)
*[[Magnetic resonance imaging|MRI]] is the imaging modality of choice for primitive neuroectodermal tumors.<ref name="pmid15165129">{{cite journal |vauthors=Shi H, Kong X, Xu H, Xu L, Liu D |title=MRI features of intracranial primitive neuroectodermal tumors in adults: comparing with histopathological findings |journal=J. Huazhong Univ. Sci. Technol. Med. Sci. |volume=24 |issue=1 |pages=99–102 |date=2004 |pmid=15165129 |doi= |url=}}</ref>
:* S-100 protein
*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.
:* Synaptophysin
=== Other Imaging Findings ===
:* Chromogranin A
*There are no other imaging findings associated with primitive neuroectodermal tumors.
 
=== Other Diagnostic Studies ===
===Imaging Findings===
*There are no other diagnostic studies associated with primitive neuroectodermal tumors.
*[[Magnetic resonance imaging|MRI]] is the imaging modality of choice for primitive neuroectodermal tumor.
*On [[Computed tomography|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 ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
*There is no consensus in treatment of PNET.
*There is no treatment for PNET.
*Chemotherapy is controversial in treatment of PNET.
*[[Chemotherapy]] is controversial in the treatment of PNET.
*Temozolomide can be added to conventional treatment of excision and radiotherapy.
*For the management of peripheral form of PNET, [[systemic]] [[chemotherapy]] has been associated with a better [[prognosis]] and is generally recommended.<ref name="AlonsoYi2017">{{cite journal|last1=Alonso|first1=Marta M.|last2=Yi|first2=Xiaoping|last3=Liu|first3=Wenguang|last4=Zhang|first4=Youming|last5=Xiao|first5=Desheng|last6=Yin|first6=Hongling|last7=Long|first7=Xueying|last8=Li|first8=Li|last9=Zai|first9=Hongyan|last10=Chen|first10=Minfeng|last11=Li|first11=Wenzheng|last12=Sun|first12=Lunquan|title=Radiological features of primitive neuroectodermal tumors in intra-abdominal and retroperitoneal regions: A series of 18 cases|journal=PLOS ONE|volume=12|issue=3|year=2017|pages=e0173536|issn=1932-6203|doi=10.1371/journal.pone.0173536}}</ref>


=== Surgery ===
=== Surgery ===
*Based on the site of the tumor, maximum resection must be performed.
*The feasibility of surgery depends on the site of the [[tumor]], at diagnosis. Maximum resection must be performed.
 
=== Radiotherapy ===
* 7 to 8 weeks of radiotherapy at a dose of 50-55 Gy is recommended <ref>{{Cite journal|last=Batsakis JG, Mackay B, el-Naggar AK|first=|date=1996|title=Ewing's sarcoma and peripheral primitive neuroectodermal tumor: an interim report.|url=|journal=Ann Otol Rhinol Laryngol.|volume=|pages=|via=}}</ref>.
 
=== Prevention ===
*There are no primary preventive measures available for primitive neuroectodermal tumor.


=== Primary Prevention ===
*There are no [[Primary prevention|primary preventive]] measures available for primitive neuroectodermal tumors.
=== Secondary Prevention ===
*There are no [[Secondary prevention|secondary preventive]] measures available for primitive neuroectodermal tumors.
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
[[Category: Oncology]]
[[Category: Oncology]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]

Latest revision as of 17:02, 14 November 2019

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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

Classification

Pathophysiology

Courtesy of image Wikipedia

Differentiating Primitive Neuroectodermal Tumor from Other Diseases

Epidemiology and Demographics

  • The incidence of PNETs is from birth to 20 years of age approximately 0.29 per 100,000.[13]
  • The prevalence of primitive neuroectodermal tumors remains unknown.
  • PNETs are more common among children.
  • PNETs are more prevalent in men than women.[14]
  • PNETs are more prevalent in Hispanic and white races.

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

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

CT

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.[22]
  • 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.[11]

Surgery

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

Primary Prevention

Secondary Prevention

References

  1. ↑ Yagnik, Vipul D; Dawka, Sushil (2019). "

    Extraskeletal Ewing's sarcoma/peripheral primitive neuroectodermal tumor of the small bowel presenting with gastrointestinal perforation

    ". Clinical and Experimental Gastroenterology. Volume 12: 279–285. doi:10.2147/CEG.S203697. ISSN 1178-7023.
  2. ↑ Rorke LB. (1983). "The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors". J Neuropathol Exp Neuro.
  3. ↑ Batsakis, John G.; MacKay, Bruce; El-Naggar, Adel K. (2016). "Ewing's Sarcoma and Peripheral Primitive Neuroectodermal Tumor: An Interim Report". Annals of Otology, Rhinology & Laryngology. 105 (10): 838–843. doi:10.1177/000348949610501014. ISSN 0003-4894.
  4. ↑ Castro, E. C.; Parwani, A. V. (2012). "Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Kidney: Two Unusual Presentations of a Rare Tumor". Case Reports in Medicine. 2012: 1–7. doi:10.1155/2012/190581. ISSN 1687-9627.
  5. ↑ Triarico S, Attinà G, Maurizi P, Mastrangelo S, Nanni L, Briganti V, Meacci E, Margaritora S, Balducci M, Ruggiero A (July 2018). "Multimodal treatment of pediatric patients with Askin's tumors: our experience". World J Surg Oncol. 16 (1): 140. doi:10.1186/s12957-018-1434-2. PMC 6044084. PMID 30005673.
  6. ↑ Zucman J, Delattre O, Desmaze C, Plougastel B, Joubert I, Melot T; et al. (1992). "Cloning and characterization of the Ewing's sarcoma and peripheral neuroepithelioma t(11;22) translocation breakpoints". Genes Chromosomes Cancer. 5 (4): 271–7. PMID 1283315.
  7. ↑ Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, Peter M; et al. (1992). "Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours". Nature. 359 (6391): 162–5. doi:10.1038/359162a0. PMID 1522903.
  8. ↑ Novo J, Bitterman P, Guirguis A (2015). "Central-type primitive neuroectodermal tumor of the uterus: Case report of remission of stage IV disease using adjuvant cisplatin/etoposide/bevacizumab chemotherapy and review of the literature". Gynecol Oncol Rep. 14: 26–30. doi:10.1016/j.gore.2015.09.002. PMC 4688884. PMID 26793768.
  9. ↑ Jürgens HF (1994). "Ewing's sarcoma and peripheral primitive neuroectodermal tumor". Curr Opin Oncol. 6 (4): 391–6. PMID 7803540.
  10. ↑ de Alava E, Gerald WL (2000). "Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family". J Clin Oncol. 18 (1): 204–13. doi:10.1200/JCO.2000.18.1.204. PMID 10623711.
  11. ↑ 11.0 11.1 Alonso, Marta M.; Yi, Xiaoping; Liu, Wenguang; Zhang, Youming; Xiao, Desheng; Yin, Hongling; Long, Xueying; Li, Li; Zai, Hongyan; Chen, Minfeng; Li, Wenzheng; Sun, Lunquan (2017). "Radiological features of primitive neuroectodermal tumors in intra-abdominal and retroperitoneal regions: A series of 18 cases". PLOS ONE. 12 (3): e0173536. doi:10.1371/journal.pone.0173536. ISSN 1932-6203.
  12. ↑ Ambros IM, Ambros PF, Strehl S, Kovar H, Gadner H, Salzer-Kuntschik M (April 1991). "MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration". Cancer. 67 (7): 1886–93. doi:10.1002/1097-0142(19910401)67:7<1886::aid-cncr2820670712>3.0.co;2-u. PMID 1848471.
  13. ↑ Visee, S; Soltner, C; Rialland, X; Machet, M C; Loussouarn, D; Milinkevitch, S; Pasco-Papon, A; Mercier, P; Rousselet, M C (2005). "Supratentorial primitive neuroectodermal tumours of the brain: multidirectional differentiation does not influence prognosis. A clinicopathological report of 18 patients". Histopathology. 46 (4): 403–412. doi:10.1111/j.1365-2559.2005.02101.x. ISSN 0309-0167.
  14. ↑ Ohba S, Yoshida K, Hirose Y, Ikeda E, Kawase T. (2008). "A supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature". J Neurooncol.
  15. ↑ G R Bunin, J D Buckley, C P Boesel, L B Rorke and A T Meadows (1994). "Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group" (PDF). Cancer Epidemiol Biomarkers Prev.
  16. ↑ Smoll NR. (2012). "Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)". Cancer.
  17. ↑ 17.0 17.1 Rud NP, Reiman HM, Pritchard DJ, Frassica FJ, Smithson WA (October 1989). "Extraosseous Ewing's sarcoma. A study of 42 cases". Cancer. 64 (7): 1548–53. doi:10.1002/1097-0142(19891001)64:7<1548::aid-cncr2820640733>3.0.co;2-w. PMID 2776115.
  18. ↑ Li X, Zhang W, Song T, Sun C, Shen Y (October 2011). "Primitive neuroectodermal tumor arising in the abdominopelvic region: CT features and pathology characteristics". Abdom Imaging. 36 (5): 590–5. doi:10.1007/s00261-010-9655-z. PMID 20959975.
  19. ↑ Bacci G, Capanna R, Orlandi M, Mancini I, Bettelli G, Dallari D, Campanacci M (1985). "Prognostic significance of serum lactic acid dehydrogenase in Ewing's tumor of bone". Ric Clin Lab. 15 (1): 89–96. PMID 3992134.
  20. ↑ Strenger V, Kerbl R, Dornbusch HJ, Ladenstein R, Ambros PF, Ambros IM, Urban C (May 2007). "Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients". Pediatr Blood Cancer. 48 (5): 504–9. doi:10.1002/pbc.20888. PMID 16732582.
  21. ↑ Xiao H, Bao F, Tan H, Wang B, Liu W, Gao J, Gao X (2016). "CT and clinical findings of peripheral primitive neuroectodermal tumour in children". Br J Radiol. 89 (1060): 20140450. doi:10.1259/bjr.20140450. PMC 4846188. PMID 26847997.
  22. ↑ Shi H, Kong X, Xu H, Xu L, Liu D (2004). "MRI features of intracranial primitive neuroectodermal tumors in adults: comparing with histopathological findings". J. Huazhong Univ. Sci. Technol. Med. Sci. 24 (1): 99–102. PMID 15165129.
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