European Journal of Cardiovascular Medicine

Overall, Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are extremely rare. In general population, the incidence of MPNST is 1/Million population per year1. However, incidence can increase to 05-42% in patients affected with Neurofibromatosis type 12. MPNST usually arise from peripheral nerves or shows differentiation towards the cells of the nerve sheath. They constitute 5-10 % of all soft tissue sarcomas and 50-70% are associated with Neurofibromatosis type 1 (NF1), the most common familial cancer-predisposing syndrome in humans3,4. The incidence of MPNST in NF1 has ranged between 02% and 29%1. Metastasis occurs in 39% of patients of MPNST and 68% die from their tumor3,4. MPNSTs can develop in any anatomical region, but the Sciatic nerve is affected most often.MPNSTs involving the Head and neck region comprise only 04-08 % of all MPNST and especially the Cranial nerves are extremely rare with only few case reports found in the Literature. Only 10-20 % cases are found within 2 decades of life. Intracranial MPNST more frequently arise from schwannomas than neurofibromas. Indeed, intracranial neurofibromas are exceptionally rare while most intracranial nerve sheath tumors are schwannomatous5. Most common intracranial MPNST are found in VIII and VII CN 6. Intra-cranial MPNST are usually sporadic arising de novo. The second most common mode of origin is from pre-existing Schwannomas whereas malignant transformation from pre-existing benign neurofibroma is extremely rare. As per the largest review of all reported cases of intra-cranial MPNST by Benedicte L’ Heureux and Issam Saliba, out of 60 cases 36 were sporadic, 16 arose from Schwannoma, only 06 arose from pre-existing benign Neurofibroma and there were only 4 cases of MPNST in association with NF-1. Moreover, only one case is reported in literature where MPNST arose from benign Neurofibroma in the orbital region6.

16 year old boy presented with history of painless and progressive proptosis of the right eye of 4 years duration. There was also gradual loss of vision in right eye. There was no history of vision disturbance in left eye or features of raised intra cranial pressure. Contrast enhanced MRI Brain and Orbit dated 26 Jan 2013 showed large heterogeneously enhancing mass in the right orbit with antero-inferior displacement of the eyeball along with displacement of intra-ocular muscles and optic nerve. These features favored Orbital Plexiform Neurofibroma.

FIGURE 1(initial MRI):

The patient underwent his first surgery in the form of Right frontal Craniotomy and excision of this mass at a private hospital in Aurangabad (Maharashtra) in March 2013. Histopathological evaluation was suggestive of Neurofibroma.

However, proptosis persisted after surgery and subsequently progressed. There was right orbito-temporalregion headache along with dull aching pain in the right eye. This was the time he reported at this center 3 years after the first surgery. On examination, multiple café au lait spots were evident over trunk, abdomen and limbs along with plexiform swelling over the right hand. He also had proptosis of right eye, complete ptosis and pthisic eye ball. There was large, ill-defined non pulsatile, non-compressible, non-tender mass palpable in the right orbito-temporal region with pthisicright eyeball pushed downwards and outwards. Visual acuity- right eye – perception of light was absent, left eye – 6/6 with no papilledema on left side. Pupils- right eye – could not be assessed, left eye – 3 mm reactive to light; Lisch nodule was present in left eye. There was no other neurological deficit.

CEMRI Brain dt 16/04/16 showeda large heterogeneous mass involving the entire orbit with anterior and inferior displacement of the eyeball. The muscles and the optic nerve displaced by the mass. The lesion measured 10 x 5 x 4.5 cm extending into the right parasellar and medial temporal lobes with displacement of the medial temporal lobe showing T1 hyperintense areas within. The greater and the lesser wings of the sphenoid bone on the right side appear thinned and stretched.

FIGURE 2 (pre-op MRI):

CT Angiography dt 29/04/2016 at AFMC Pune showedIntra-orbital heterogeneously enhancing lesion seen in the retro-ocular compartment of the right eye features suggestive of Plexiform Neurofibroma of size 5.8 x 3.6 x 3.2 cm with intracranial extension measuring 5.9 x 7.5 x 6.8 cm. The intracranial component seen abutting and displacing the right basifrontal cortex, laterally the Temporal lobe and on the medial aspect compressing and causing effacement of theright cavernous sinus. The lesion appeared to cause pressure erosion of the greater wing of sphenoid and sella, indenting the brainstem, causing effacement of the cisternal spaces and abutting the basilar artery. 

He was taken up forRight Fronto-Temporo-Orbito-Zygomatic Craniotomy. Per op findings suggestedpinkish yellow, extra-axial intracranial tumor extending into the right orbit. The tumor was rubbery to firm in consistency, not suck able, notamenable to CUSA and moderately vascular. Tumor was densely adherent to dura and right pthisis bulbi. Post-operative course was uneventful and subsequently discharged.

FIGURE 3 (post-op CT):

Histo-pathology evaluation at this stage suggested neurofibroma.

FIGURE 4(initial HPE):

(Neurofibroma with S-100 IHC positive)

The ptosis settled post-surgery. 02 months later he presented with insidious onset diminution of vision in left eye of 10 days duration. On examination perception of light and projection of rays were present in left eye.

CE MRI Brain showed increase in the size of previous residual lesion with involvement of both optic nerves and the optic chiasm.

He then underwent exploration and maximal safe resection through sub-temporal approach. Intra-op findings suggestedlarge,tough, tenacious, fibrous, tumor, non-suck able, not amenable to CUSA, moderately vascular tumor which was adherent to the brainstem. Also branches of basilar artery were enmeshed within and adherent to the tumor. So a maximal safe resection was done. Intra-op Frozen study was reported as Recurrent Spindle cell tumor.

Final Histo-pathology evaluation reportedwasspindle cellLow Grade Malignant Peripheral Nerve Sheath Tumor. Immune-histochemistry markers used were SMA (-), S-100 (+) and Ki-67 index (30-35%).

FIGURE 5 (FINAL HPE):

(Ki-67 IHC showing low grade malignancy)

Post-op MRI showed residual lesion and in view of this HPE report, he was evaluated along with Radiation Oncologist and planned for 60 Gyradiation. However, after 40 Gy of irradiation there was no significant change in the lesion and therefore radiotherapy was stopped by Radiation Oncologist

MPNST is defined as Spindle cell soft tissue Sarcoma arising from a nerve or a nerve sheath tumor that demonstrates neural differentiation. The World Health Organization (WHO) created this terminology to replace previous terminologies like neurofibrosarcoma, neurogenic sarcoma, malignant neurilemoma, malignant Schwannoma and malignant neurofibroma.

Malignant Peripheral Nerve Sheath Tumors (MPNST) are extremely rare. In general population, the incidence of MPNST is 1/Lac population per year¹.  However, incidence can increase to 05-42% in patients with Neurofibromatosis type 1². MPNST usually arise from peripheral nerves or somatic soft tissues. They constitute 5-10 % of all soft tissue sarcomas and 50-70% are associated with neurofibromatosis type 1 (NF1), the most common familial cancer-predisposing syndrome in humans ^3,4. The incidence of MPNST in NF1 has ranged between 02% and 29%¹. The life time risk of MPNST in patients with NF-1 is estimated to beapproximately 10% ^7,8.MPNST generally occur in adulthood, typically between ages 20-50 years whereas 10-20% of cases have been reported in the first 2 decades⁹. MPNSTs can develop in any anatomical region, but the Sciatic nerve is affected most often. MPNSTs involving the head and neck region comprise only 04-08 % of all MPNST and especially the cranial nerves involvement is extremely rare with only few case reports and small case series found in the literature. Rapid tumor enlargement is more common in patients with NF1-associated MPNST^10,11.

Intracranial MPNST more frequently arise from schwannomas than neurofibromas. Indeed, intracranial neurofibromas are exceptionally rare while most intracranial nerve sheath tumors are schwannomas ⁵. Most common intracranial MPNST are found in VIII cranial nerve^6.  

In retrospective analysis of intra cranial MPNST by Le’Hereux and Saliba which included 31 case reports and short case series comprising 60 cases, the incidence of Cranial nerve MPNST were: VIII CN: 60% ; V CN: 27%, VII CN 10%; IIICN:  6.7 %; IV CN: 1.7%; VI CN: 1.7 %⁶. This is probably related to the thickness of the nerve and the prevalence of benign intra cranial schwannomas ⁶.

When MPNST occur in the orbital region, most common origin is from ophthalmic (frontal branch) division of the V CN¹².

Neurofibromas are rare tumors of the Orbit comprising 0.6-2.4 %. Plexiform subtype is the most common (50% of orbital neurofibromas). Other types are diffuse and localised. Plexiform type is most common to progress to MPNST ¹³.

MPNST have three recognized etiologies-tumors may occur in association with NF (equal propensity of NF 1 and NF 2 to give rise to MPNST⁶,⁸), may be consequent to radiation (conventional or SRS) or may be sporadic ⁶.

In L’Heureux and Saliba’s analysis of 60 intra-cranial MPNST, 36 arose de novo, 16 arose from pre-existing Schwannoma, only 06 (10%) arose from malignant transformation of Neurofibroma whereas origin of the remaining 04 was unknown⁶. Moreover, only 4 of 60 patients (06.66%)had  Neurofibromatosis type 1 and equal number had Neurofibromatosis type 2⁶.

MPNSTs are highly malignant tumors that grow rapidly along nerves, infiltrate surrounding tissues and develop hematogenous metastasis. Metastasis occurs in 19-39% of patients of MPNST and 68% die from their tumor ^3,4. Alone, this rapid evolution may differentiate MPNST from its benign counterpart. Bowers et al found that symptom onset to diagnosis is usually 2 to 3 years in benign schwannoma of CN V compared to 2.8 months for MPNST of CN V¹⁴. 

MPNSTs have been known to develop Hematogenous distant metastases (most commonly to Lungs; other sites being Bones and Liver³). However, among the eleven reported cases of CN MPNSTs (Bowers et al¹⁴) that developed metastases, it was specified in three of these cases that metastases were pial or dural based in the spinal cord hence a consequence of CSF dissemination¹⁴.

MRI study does not allow confident distinction between benign and malignant peripheral nerve sheath tumors. A size more than 5 cm, infiltrative margins and marked signal heterogeneity, adjacent structure compression and local invasion are features which favor MPNST¹⁷.

The diagnosis of MPNST requires biopsy and remains controversial due to its lack of specific morphological criteria and immunohistochemical or molecular tests. Among sarcomas, a diagnosis of MPNST is often one of exclusion. Because no cytological feature or set of features appears to be specific, a pathological diagnosis of MPNST remains challenging ⁶.

Histological features are alternating hypo and hyper cellular areas, asymmetrical and fusiform spindle cells, palisade arrangement of hyperchromatic nuclei, peri/intra neural spread, sub-endothelial vessel infiltration and areas of geography like necrosis¹⁵.There are three Histological sub types described- spindle cell (most common), epithilioid and rhabdomyoblastic⁶.

Immunohistochemical markers are S-100, CD56, CD117, CD 34, CD 45, NSE, synaptophysin and vimentin. S-100 is considered to be the best marker (50-90% cases).p53 is helpful in differentiating MPNST from neurofibroma; proliferation markers MIB 1 and Ki 67 index are indicators of higher grade malignancy and adverse prognosis ¹⁵.

Standardized grading systems for MPNSTs are presently lacking. The French system (FédérationNationale des Centres de LutteContre le Cancer [FNCLCC]) and the WHO grading system are the most commonly used systems for grading soft tissue sarcomas. However, these systems have no prognostic value for few sarcomas including MPNST ⁶.

Rodriguez et al¹⁶ suggest updates to the WHO classification of tumors of cranial and paraspinal nerves, in particular MPNST, because of differences in their evolution and differential diagnosis.They proposed seven categories: low-grade MPNST, high-grade MPNST, epithelioid MPNST, MPNST with divergent differentiation, MPNST ex-schwannoma, malignant melanotic schwannoma, and perineural MPNST.

All MPNST belong to WHO grades II-IV⁶.

Some authors have advocated the use of a simpler practical approach to MPNSTs by dividing tumors into low grade and high grade⁶.

Since cases of intracranial MPNST are limited, their management is based on the experience gained from the management of peripheral MPNSTs. The management of intracranial MPNST is therefore primarily surgical. Gross total resection of intracranial MPNST has been shown to significantly influence overall survival and relates inversely with local recurrence.The treatment goal should be complete surgical tumor resection with preservation of neurological function. However, as MPNST can extend considerably along nerves and given the location of CN MPNST and the tenacious nature of tumor, complete surgical resection can be challenging and is not always feasible¹. However, the rate of gross total resection on cranial nerve MPNST found in literature is very low (15%)⁶. The intra-op findings found in literature are size > 5 cm, globoid or fusiform shape, areas of cystic change and necrosis, tan gray in color, consistency fleshy and firm-hard, may have fibrous pseudocapsule, invasion in surrounding structures⁹.

The role of adjuvant Radiotherapy remains controversial since radiation may be implicated in the pathogenesis of MPNSTs, as previously discussed. Radiation therapy appears to be an important adjunct to surgery in improving local control of extracranial MPNST. Some efficacy has been shown in univariate analysis but not in multivariate analysis⁶.The majority of patients received a dose of 50–60 Gy. In Le’Heurex and Saliba analysis, patients that were treated with radiotherapy had a longer survival rate⁶.

Treatment using Chemotherapy is controversial.Numerous Chemotherapy regimens have been used against MPNST but the clinical benefits have been variable and inconclusive. When combined with surgery and radiotherapy, no significant survival benefit has been observed ^3,6.

Thus in patients with large orbital region intra-cranial MPNST which cannot be removed completely due to critical location, maximal safe surgery with high dose radiotherapy remains the mainstay of treatment⁶.

The prognosis in intra-cranial MPNST is not very good as the recurrence rate is 45%, mortality is 60%, mean survival is 9.2 months, one year survival rate is 33%⁶. 39% is the incidence of Metastasis. Poor prognostic factors are association with NF-1, size larger than 5 cm and incomplete resection¹⁸.

Intra-cranial MPNST of the orbital region are very rare. When present, most of the times arise from Schwannoma. Intra-cranial MPNST arising from pre-existing Neurofibroma is extremely rare and a high grade malignancy with poor prognosis. Complete excision should be the goal of Surgery which is the mainstay of Treatment. However, due to the tenacious nature of tumor and intimate relation with critical neurovascular structures, this may not always be feasible. When such tumors cannot be excised completely, high dose Radiation is a useful adjunct.

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