Case Report

Primary intracranial peripheral PNET” A case report and review Kiranchand Velivela, Alugolu Rajesh, Megha Shantveer Uppin1, Anirrudh Kumar Purohit Departments of Neurosurgery and 1Pathology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India

Abstract Address for correspondence: Dr. Alugolu Rajesh, Department of Neurosurgery, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad-500 082, Telangana, India. E-mail: [email protected] Received : 08‑09‑2014 Review completed : 03‑10‑2014 Accepted : 05‑12‑2014

The site of origin of primitive neuroectodermal tumors (PNETs) is quite varied and has significant influence on the prognosis. We report a case of intracranial peripheral PNET/ Ewing’s sarcoma arising from the superior tentorial surface in a 13‑year‑old girl. Gross total excision of the tumor was done. We have discussed the distinction between central nervous system PNET (CNS PNET) and Intracranial Peripheral PNET (pPNET/ES) as their treatment and prognosis varies radically. A review of literature shows that prognosis is better in intracranial pPNET/ES. Key words: CD 99, central nervous system PNET, intracranial, peripheral PNET (pPNET/

ES), tentorium

Introduction Primitive neuroectodermal tumors (PNET) of the central nervous system (CNS) are a heterogeneous group of embryonal tumors that occur predominantly in children and adolescents and show aggressive clinical behavior.[1,2] They may arise in the cerebral hemispheres, brain stem, or spinal cord.[1] PNETs arising outside the CNS are grouped into peripheral PNET/Ewing’s sarcoma family of tumors (pPNET/ES). They can occur in both osseous and extraosseous tissues, including intracranial (extraparenchymal), showing characteristic translocation t(11;22) (q24;q12).[3] A 13‑year‑old girl presented with occipital headache of 3 months duration, which increased with coughing and was associated with blurred vision. Neurologic examination revealed normal visual acuity, loss of color vision and bilateral papilledema. Magnetic resonance imaging (MRI) demonstrated a solid‑cystic lesion in

the left temporoparietal and occipital regions attached to tentorium. The solid component was isointense on both T1W and T2W and enhanced on Gd‑enhanced T1W images. There was mass effect over the midbrain and ipsilateral temporal and occipital horns with midline shift. Perilesional edema was minimal [Figure 1a‑f]. With the patient in prone position supported with horseshoe headrest, occipito‑temporo‑parietal

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Figure 1: MRI T2W imaging (a) axial, (b) sagittal and (c) coronal showing lesion in the left temporoparietal and occipital regions, attached to the tentorium which is heterogenous with cystic component and causing mass effect over the midbrain. MRI contrast scans (d) axial, (e) sagittal and (f) coronal show heterogenous enhancement of the lesion

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craniotomy was performed. The tumor was attached to the tentorium and was grayish white, firm and moderately vascular with well‑defined plane of cleavage from the surrounding brain parenchyma. Cysts were noted medially and laterally which were dissected along the plane of cleavage. Gross total excision of the tumor was done. The tumor was found to be attached to the tentorium. Postoperative period was uneventful. Postoperative MRI revealed no residual tumor [Figure 2a‑f]. Bone scan performed in the postoperative period was negative for any hotspots. Postoperatively the patient received local radiotherapy (50 Gy in 25 fractions over 30 days to the tumor bed) and was doing well with no evidence of disease after 24 months. Chemotherapy was not given as the parents did not give consent for chemotherapy. Microscopically the tumor showed small round blue cells with oval to elongated nuclei having vesicular chromatin [Figure 3a and b]. There was no evidence of neuroblastic differentiation with rosettes/necrosis/

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Figure 2: Postoperative MRI T2W imaging (a) axial, (b) sagittal and (c) coronal showing gliotic changes with enlargement of left occipital horn and no residual tumor. MRI contrast scan (d) axial, (e) sagittal and (f) coronal shows no tumor suggesting gross total excision of tumor

calcification. Immunohistochemical examination demonstrated CD99 and NSE positivity in tumor cells [Figure 3c]. Immunohistochemistry with CD34, GFAP, EMA, Synaptophysin was negative and INI‑1 expression was retained. Fluorescence in situ hybridization with a EWSR1 break apart probe (Vysis, Abbott diagnostics) showed > 15% of split signals confirming the diagnosis of pPNET [Figure 3d]. CNS and peripheral PNETs though cannot be distinguished on morphology have distinct genetic features [Table 1]. The MIC2 gene product (CD99), although expressed in nearly all pPNET,[7] is not specific and can also be detected in other small, blue round cell tumors like rhabdomyosarcoma, desmoplastic small round cell tumor, lymphoblastic lymphomas. However, the pattern of staining is often cytoplasmic, rather than the distinct membranous staining typical of pPNET. Central PNETs are reported to be negative for CD99 staining. Cytogenetic and molecular biologic characterization of ES/pPNET has revealed a consistent chromosomal

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Figure 3: (a) The cells lining the leptomeninges. (b) The cells are small round with vesicular nuclei H and E x400. (c) Immunohistochemical positivity for CD 99. HRP Polymer CD 99; 400. (d) FISH with EWS-FLI break apart probe showing the positive breakapart signals. (Arrowheads)

Table 1: Differences between cPNET and pPNET Location MR imaging

CD 99 Molecular abnormalities Radiotherapy Chemotherapy

CNS PNET

pPNET

Supratentorial Intra‑axial

Supra/infratentorial Extra‑axial (but larger lesions may obscure distinction between an intra‑axial or extra‑axial lesion) Lobulated, usually dura‑based, heterogeneous on T1 and T2 and heterogeneous intense enhancement.[4] Usually no dissemination Positive Chromosomal translocation‑t (11;22) (q24;q12) in most cases Variant translocations‑t(21;22), t(7;22), and t(17;22) Local radiotherapy Alternating cycles of cyclophosphamide, doxorubicin, vincristine and ifosfamide, etoposide[6]

T1 hypo, T2 heterogeneous lesions with calcification (50‑70%) and heterogeneous enhancement May have leptomeningeal dissemination Negative Non‑random cytogenetic gains and losses No 17q abnormalities Local and craniospinal irradiation Cisplatin, lomustine, and vincristine (or) alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine[5]

CNS PNET - Central nervous system primitive neuroectodermal tumors, pPNET - Intracranial peripheral primitive neuroectodermal tumors

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translocation t(11;22) (q24;q12) found in up to 90‑95% of all cases, resulting in a chimeric fusion of the EWS gene on the long arm of chromosome 22 and the human homolog of the FLI1 gene on the long arm

of chromosome 11.[8,9] Variant translocations include t(21;22), t(7;22), and t(17;22), all of which involve the EWS gene on 22q12.[7] It is important to differentiate pPNET/ES from central PNETs because the treatment

Table 2: Reported cases of intracranial peripheral PNET

Case Author (year) no

Age/sex Symptoms and signs

Location

Molecular Treatment diagnosis

1

Jay et al., 1996

4/M

NA

Cerebellum

+

2

Papotti et al., 1998

30/F

Headache, vertigo

Rt frontal duramater

+

3

Katayama et al., 1999

5/M

Tentorium

ND

4

Antunes et al., 2001

6/M

Vomiting, left abducent nerve palsy Lethargy, vomiting

Lt frontal duramater

+

5

Kalmarides et al., 2001

34/F

Lt CP angle

ND

6

Niwa et al., 2001

Frontal duramater

ND

Gross total excision

Patient expired on 8th postoperative day

7

Simmons et al., 2001

Rt CP angle

ND

Biopsy done Radiotherapy

Expired 13 months after surgery

8

Elias et al., 2002

Cavernous sinus

NA

Transsphenoidal debulking Radiotherapy and chemotherapy

9

Dedeurwaerdere et al., 2002

Diagnosed to have Ewing’s sarcoma of distal left fibula 2 months later with multiple metastases involving spine, ribs and extremities No evidence of disease at 12 months No evidence of disease at 8 years

10

Vertigo, pulsatile tinnitus, gait disturbance, Rt nystagmus 5 months/F Exophthalmos, bloody nasal discharge 67/F Rt facial pain, Rt sided hearing loss, slurred speech 27/M Left retro orbital headache and 3rd nerve paresis

17/M

Headache

12/M

11

Utsunomiya et al., 2004

7/M

12

D’Antonio et al., 2004

50/F

13

Bunyaratavej et al., 2005

17/M

Headache, Lt neck, arm, chest paresthesias Headache, vomiting, Rt abducent nerve palsy Headache, vomiting, drowsiness Raised ICP

17/M

Raised ICP

46/M

Headache, nausea, vomiting, Right ophthalmoplegia, Rt ptosis and PL positive in Rt eye

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Idrees et al., 2005

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Rt frontal duramater with delayed contralateral CP angle recurrence Rt frontal duramater Frontal duramater

Rt parieto‑ temporal duramater Rt fronto parietal region Lt temporal region Rt cavernous sinus

+

+

ND

Gross total excision Chemotherapy, Radiotherapy Gross total excision Radiation and chemotherapy given after local recurrence Gross total excision Radiotherapy and intrathecal chemotherapy Gross total excision Radiotherapy and chemotherapy Sub‑total excision Radiotherapy

Follow up

Gross total excision Local radiotherapy (Sub‑total excision of CP angle recurrence followed by chemotherapy and craniospinal radiation) Gross total excision Chemotherapy and craniospinal Radiotherapy Gross total excision Radiotherapy and chemotherapy

+

Gross total excision

ND

Gross total excision

ND

Gross total excision

 _

Tumor biopsy Chemotherapy and radiotherapy

NA

Disease free for 7 years Died 10 years after diagnosis due to metastatic disease Disease free follow up of 7 years NA

Follow up after 1 year showed no recurrence

No evidence of disease at 27 months No evidence of disease 2 years after surgery

No evidence of disease 12 months after surgery No evidence of disease at 12 months No evidence of disease at 24 months NA

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Table 2: Contd....

Case Author (year) no

Age/sex Symptoms and signs

Location

Molecular Treatment diagnosis

16

Khusen et al., 2005

13/F

Orbital apex syndrome

Rt cavernous sinus

ND

17

Mazur et al., 2005

8/F

Headache, Rt tentorium nausea, vomiting

+

7/F

Headache, vomiting

Rt frontal lobe

+

Headache, Lt III, V1, V2 and VI cranial nerve involvement Headache, diplopia, Lt partial homonymous hemianopia

Lt cavernous sinus

+

Rt occipital parafalcine region

+

Partial resection Chemotherapy and radiotherapy

Bifrontal tumor extending on both sides of falx cerebri Rt tentorium extending into both supratentorial and infratentorial compartments Rt frontal falcine

+

Gross total excision Chemotherapy and radiotherapy

+

Incomplete excision Chemotherapy and radiotherapy

No evidence of disease 12 months after diagnosis

NA

Gross total excision Radiotherapy and chemotherapy Open biopsy Chemotherapy and radiotherapy

No evidence of disease after 20 years

18

19

Atabib et al., 2006

48/F

20

Mobley et al., 2006

21/M

21

Kazmi et al., 2007

7/F

Headache

22

Navarro et al., 2007

3/M

Acute onset headache, vomiting

23

Asano et al., 2007

24

Kobayashi et al., 2008

10/M

Rt lower cranial nerve palsies

Rt jugular foramen

25

Furuno et al., 2008

15/M

Headache

26

Bano S et al., 2009

11/F

Rt fronto temporal region Anterior falx

27

dos Santos Rubio et al., 2010

10/F

Midline frontal scalp swelling, headache, giddiness, epiphora, diplopia Headache, Lt CP angle vomiting, diplopia Lt V, VI, VII, VIII and XI cranial nerve involvement

21 months/ Raised ICP M

+

ND

+

+

Tumor biopsy Radiotherapy and chemotherapy

Follow up

Partial excision Radiation and chemotherapy Extent of resection not mentioned Radiotherapy and chemotherapy Tumor debulking Radiotherapy and chemotherapy

Metastatic workup detected mass at thyroid. Underwent total thyroidectomy and ERT to thyroid bed and mediastinum. Hip metastasis at 16 months. Died at 18 months No evidence of disease at 2 years NA

Residual tumor at 14 months postsurgery without neurological deficits Imaging at 18 months postsurgery detected intracranial disease and metastasis to multiple cervical and thoracic vertebrae 21 months‑  Chemotherapy and craniospinal radiation Received 48 weeks of systemic chemotherapy

Gross total excision Radiotherapy and chemotherapy Sub‑total excision

MRI showed complete remission of lesion 12 months after diagnosis No evidence of disease 6 months after diagnosis NA

Incomplete resection Chemotherapy and radiotherapy

Patient doing well 6 months after diagnosis

Contd.....

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Table 2: Contd....

Case Author (year) no

Age/sex Symptoms and signs

28

Antonelli et al., 2011

37/M

Presented in comatose state after 2 weeks of headache

29

Burkhardt et al., 2011

16/M

Rt brachiofacial hemisyndrome

30

Choudhury et al., 2011

11/F

31

Patibandla MR et al., 2011

32

Tanboon et al., 2012

Headache, vomiting, Lt temporal scalp swelling, 11 months/F Proptosis and Rt 6th nerve palsy 22/F

Rt frontal skull mass, Raised ICP

Location

Molecular Treatment diagnosis

Follow up

Rt fronto temporal dura with recurrence at temporal region after 1 year Lt frontoparietal bleed

+

Gross total excision Complete excision of recurrence Radiotherapy

Patient doing well 17 months after 1st surgery

_

No evidence of disease 3 months after surgery

Lt temporo‑ parietal

+

Gross total excision Radiotherapy and chemotherapy NA

Rt cavernous sinus

+

Rt frontal duramater

+

Debulking done One cycle of chemotherapy Gross total excision

NA

Patient died on postoperative day 37 Patient developed multiple intracranial metastases at 2 months and died 6 months after initial operation

NA - Not available, ND - Not done, + - Positive,− - Negative, CP angle - Cerebellopontine angle, PNET - Primitive neuroectodermal tumors, ICP – Intracranial pressure

and prognosis are radically different. The 5‑year progression‑free and overall survival in supratentorial PNETs is 37% and 53%.[10] In contrast, many patients with pPNETs as reported in literature achieved long‑term disease‑free survival [Table 2]. Long‑term disease‑free survival could be achieved with aggressive surgical resection, local radiotherapy and chemotherapy in primary intracranial pPNET/ES.

References 1. 2. 3.

4.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO Classification of tumours of the central nervous system. 4th ed. IARC: Lyon; 2007. p. 141-6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114:97‑109. Weiss SW, Goldblum JR. Ewing’s sarcoma/pnet tumor family and related lesions. In: Weiss SW, Goldblum JR, editors. 5th ed. Weiss and Goldblum: Enzinger and Weiss’s SoftTissue Tumors. Philadelphia: Mosby Elsevier; 2008. p. 945‑87. Pekala JS, Gururangan S, Provenzale JM, Mukundan S Jr. Central nervous system extraosseous Ewing sarcoma: Radiologic manifestations of this newly defined pathologic entity. AJNR Am J Neuroradiol 2006;27:580‑3.

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5. Greenberg HS, Chamberlain MC, Glantz MJ, Wang S. Adult medulloblastoma: Multiagent chemotherapy. Neuro Oncol 2001;3:29‑34. 6. Womer RB, West DC, Krailo MD, Dickman PS, Pawel BR, Grier HE, et al. Randomized controlled trial of interval‑compressed chemotherapy for the treatment of localized Ewing sarcoma: A report from the Children’s Oncology Group. J Clin Oncol 2012;30:4148‑54. 7. Hasegawa SL, Davison JM, Rutten A, Fletcher JA, Fletcher CD. Primary cutaneous Ewing’s sarcoma: Immunophenotypicand molecular cytogenetic evaluation of five cases. Am J Surg Pathol 1998;22:310‑8. 8. Delattre O, Zucman J, Melot T, Garau XS, Zucker JM, Lenoir GM, et al. The Ewing family of tumors‑A subgroup of small‑round‑cell tumors defined by specific chimeric transcripts. N Engl J Med 1994;331:294‑9. 9. Sandberg AA, Bridge JA. Updates on cytogenetics and molecular genetics of bone and soft tissue tumors: Ewing sarcoma and peripheral primitive neuroectodermal tumors. Cancer Genet Cytogenet 2000;123:1‑26. 10. Reddy AT, Janss AJ, Phillips PC, Weiss HL, Packer RJ. Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 2000;88:2189‑93. How to cite this article: Velivela K, Rajesh A, Uppin MS, Purohit AK. Primary intracranial peripheral PNET" - A case report and review. Neurol India 2014;62:669-73. Source of Support: Nil, Conflict of Interest: None declared.

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Primary intracranial peripheral PNET"--a case report and review.

The site of origin of primitive neuroectodermal tumors (PNETs) is quite varied and has significant influence on the prognosis. We report a case of int...
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