Malignant peripheral nerve sheath tumour transformation of histological benign vestibular schwannoma after stereotactic radiosurgery in patients without neurofibromatosis

  1. Orlando De Jesus 1,
  2. José G Sánchez Jiménez 1,
  3. George Santiago Quiñones 2 and
  4. Román Vélez 2
  1. 1 Neurosurgery, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
  2. 2 Pathology and Laboratory Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico
  1. Correspondence to Dr Orlando De Jesus; drodejesus@aol.com

Publication history

Accepted:22 Oct 2021
First published:11 Nov 2021
Online issue publication:11 Nov 2021

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Stereotactic radiosurgery (SRS) poses a minimal but important risk for tumour transformation, typically occurring 8–10 years after the treatment. Malignant peripheral nerve sheath tumour (MPNST) is the most common tumour arising from a vestibular schwannoma treated with SRS, with only 14 cases previously reported. We present the fifteenth case and describe its evolution and clinical course. A 56-year-old man without a history of neurofibromatosis was diagnosed 9 years prior with a vestibular schwannoma. SRS to the residual tumour was given 3 months later. During the current hospitalisation, he was reoperated where histology confirmed a MPNST. All 15 MPNST cases were analysed, showing a 77% female predominance presenting a malignant transformation at a mean age of 51. The diagnosis was made at a mean time of 74 months after SRS. The mean survival time after diagnosis was 16 months. MPNST arising from benign vestibular schwannoma after SRS treatment is an uncommon but devastating complication.

Background

Vestibular schwannoma (VS) is a benign tumour that rarely becomes malignant. These tumours can be observed due to their slow growth or can be treated with surgery, radiotherapy or a combination of both. Stereotactic radiosurgery (SRS) had been accepted as a safe and effective treatment for VS.1–4 Frischer et al reported radiological tumour control rates of 92%, 91% and 91% at 5, 10 and 15 years after SRS and recommended SRS at an early stage as the primary treatment for small-to-medium sized VSs.5 Most VSs display typical radiographic and clinical features; therefore, a biopsy is generally not considered before establishing the radiotherapy treatment plan.6 In the past, some VS cases were treated with fractionated radiotherapy at centres where SRS was unavailable. SRS given using a Gamma Knife (GK), Cyberknife or Linac is the accepted treatment to reduce radiation effects on nearby structures. A marginal dose of 12–13 Gy is used at most centres, with adequate tumour control rates.

Radiation effects pose a minimal but important risk for the malignant transformation of a tumour, occurring typically 8–10 years after the treatment. We reviewed the literature concerning the malignant transformation of VS after SRS and found few reported cases of histologically confirmed VSs treated with SRS that transformed into malignant tumours. There are only 14 reported cases of malignant peripheral nerve sheath tumours (MPNST). We present the fifteenth case and describe its evolution and clinical course.

Case presentation

A 56-year-old man without a history of neurofibromatosis (NF) presented to our hospital due to recent episodes of headaches. Nine years prior, he was evaluated at an outside institution due to a 2-year history of right hearing impairment and vertigo where the neuroradiological studies showed a heterogeneous enhancing right cerebellopontine angle tumour entering the right internal auditory canal suspicious for a VS. The tumour had a volume of 14.3 cm3 and was operated subtotal by a retrosigmoid approach where histology confirmed a benign schwannoma without cellular atypia or mitosis. Three months later, SRS using GK was given to the residual tumour (1.44 cm3). The radiation dose had a marginal dose of 12 Gy to 50% isodose with a maximum dose of 24 Gy. The tumour remained stable for the next 8 years on yearly follow-up brain MRI (figure 1).

Figure 1

Brain MRI with contrast showing that the tumour had remained stable for 8 years, measuring 2.3 cm × 2.0 cm × 2.0 cm after the stereotactic radiosurgery.

Investigations

At the time of our evaluation, his neurological examination demonstrated a complete right hearing loss with intact facial and lower cranial nerve function. We performed a new MRI and compared it to his last MRIs performed 9 and 24 months prior. Comparing the three studies, the enhancing mass did not increase in size; however, it developed a posterior cystic area without a significant compression on the brainstem nor hydrocephalus (figure 2). He was sent home to have a new MRI in 6 months; however, 3 weeks later, he returned with significant ataxia and slurred speech. Head CT scan showed an increased size of the tumour and the cyst (figure 3). The enlargement caused a displacement of the fourth ventricle producing obstructive hydrocephalus.

Figure 2

Brain MRI with contrast during the current evaluation shows that the tumour had increased in size, measuring 3.5 cm × 3.0 cm × 2.6 cm, with a posterior non-enhancing area compatible with cystic changes (left). The T2-weighted image shows vasogenic oedema throughout the cerebellum and posterior brainstem (right). There was mass effect on the fourth ventricle but no ventriculomegaly.

Figure 3

Head CT scan without contrast shows an increase in the tumour and cyst.

Treatment

The patient had an emergency ventriculoperitoneal shunt that same night. He improved clinically, but a week later, the symptoms reappeared, associated with lower cranial nerve dysfunction requiring intubation. A head CT scan did not show ventriculomegaly, but the tumour had grown larger, and the cyst had expanded further, forming three separated larger cysts (figure 4). The following day, he was operated on to drain the cysts and partially remove the tumour. Approximately 90% of the tumour was removed. Postoperative head CT scan confirmed the removal of the majority of the mass and the cysts (figure 5).

Figure 4

Head CT scan a week after the shunt placement shows a further tumour expansion and three larger cysts. There is significant compression of the brainstem and cerebellum.

Figure 5

Postoperative head CT scan showed removal of the majority of the mass and the cysts.

Microscopically, the tumour was composed of fairly monotonous spindle cells with hyperchromatic nuclei and a fascicular growth pattern. Immunohistochemistry showed a diffuse weak-to-moderate positivity for CD56, focal positivity for S-100 and diffuse positivity for INI1. The Ki67 proliferation marker was positive in up to 100% of neoplastic cells, and phosphohistone-H3 labelling revealed a mitotic rate of more than 50 mitoses per 10 high-power fields. Both markers favour the high-grade malignant nature of the tumour. Negative markers included pankeratin (AE1/AE3), desmin, glial fibrillar acidic protein, and epithelial membrane antigen. The histology and immunohistochemistry were consistent with a MPNST (figure 6).

Figure 6

(A) H&E microphotograph showing dark cellular areas alternating with lighter, less cellular areas (red arrow, H&E ×100). (B) Magnification of the higher cellular area (H&E ×400). (C) The Ki67 proliferation marker is positive in nearly 100% of neoplastic cells (brown nuclear stain, ×100). (D) Phosphohistone H3 highlights the high mitotic activity showing more than 50 mitoses per 10 high-power fields (red arrowhead, ×200). (E) CD56 variable strength positivity (brown membrane stain ×200). (F) S-100 focal positive (red nuclear and cytoplasmic stain ×100). Histology and immunohistochemistry are consistent with a malignant peripheral nerve sheath tumour.

Outcome and follow-up

A tracheostomy was performed because of prolonged intubation. He improved neurologically, and a brain MRI was repeated 2 weeks later due to the malignant diagnosis, which showed regrowth of the tumour, more than double in size from the study 2 weeks prior (figure 7). The patient and his daughter were recommended adjuvant SRS to the tumour; however, they opted to stay home and receive hospice care due to the tumour’s poor prognosis.

Figure 7

Brain MRI 2 weeks after tumour resection showing regrowth of the tumour, measuring 5.0 cm × 4.0 cm × 2.4 cm.

Discussion

Radiotherapy given to a tumour may produce adverse effects, including malignant transformation of the tumour or the appearance of new tumours. The malignant transformation of a tumour may be caused by the radiation’s direct effect or the tumour’s natural history. Muracciole and Regis calculated that 20 years after radiotherapy, the patient risk of a malignant transformation was <0.1% when treated by SRS compared with a 10% risk with traditional external radiotherapy.7 In 2018, the Congress of Neurological Surgeons presented a level 3 evidence-based recommendation that patients should be informed that there is a minimal risk of a malignant transformation of a VS after SRS.8 The clinician should emphasise to the patient the importance of long-term follow-up with imaging studies to patients who receive SRS.5–7 9–14 SRS should be used cautiously in young individuals due to the long latency in developing a tumour transformation.4 9 11 13

Several cases of VS transformation after radiotherapy have been reported. Most commonly, the VS transforms into a MPNST. The majority of the cases occurred following SRS. Only four cases after non-SRS radiotherapy had been reported.15–18 Approximately 66% of the MPNST cases occur in patients with NF type 1; however, its association with NF2 is rare.19 20 For VS tumours that developed SRS-induced MPNSTs, the latency varies between 0.7 and 19 years with a maximum dose of 20–35 Gy and a marginal dose of 12–17 Gy.21

We reviewed the literature concerning the malignant transformation of VS after SRS. Only 14 cases who developed a MPNST after receiving SRS to a histologically confirmed VS had been reported in the literature (table 1).3 5 9–11 13 22–27 All cases involved GK SRS, except the case by Puataweepong et al involving Linac hypofraction in six sessions for 80% at 30 Gy and the case by Peker et al that received Cyberknife.10 26 We presented the fifteenth case of a SRS-induced MPNST originating from a histologically confirmed VS. For a true malignant transformation secondary to radiation, the Cahan criteria must be satisfied: (1) histologic diagnosis of benign condition before irradiation, (2) malignancy occurs within the radiation field, (3) prolonged latency before development of malignancy (>5 years) and (4) histologic diagnosis of malignancy.28 Two of the included cases did not have an initial pathology before SRS, but they probably represent a true malignant transformation due to the long latency and a benign VS pathology obtained after the SRS.3 5 The case by Hasegawa et al did not have an initial pre-SRS pathology, but a surgery done 52 months after the GK SRS showed a histologically benign tumour; however, 14 months later, another surgery showed malignant transformation into a MPNST, dying 13 months later.3 The case presented by Frischer et al had surgery done 8 years after the SRS, which was reported as a benign VS but with some areas of increased cellularity, brisk mitotic activity and MIB-1 labelling index of 35%; however, 8 months later, a repeat surgery showed a malignant transformation into a MPNST.5 The three cases presented by Li et al do not have a prolonged latency before the development of malignancy (>5 years) but do have a benign VS pathology before the SRS.27

Table 1

Published MPNST cases arising from benign VS after SRS in patients without neurofibromatosis

Author Year Sex Age at malignant transformation Initial size Treatment Radiation dose Time after SRS Survival after Dx of MPNST
Shin et al 13 2002 F 32 years 30 mm S, GK, S 17 Gy 50% 72 m 10 m
Hasegawa et al 3 2005 F 61 years 4 cm3 GK, S ×5 12.7 Gy 66 m 13 m
Akamatsu et al 22 2010 F 81 years 5.1 cm3 S, S, GK, S 12 Gy (max 24.4 Gy) 96 m NR
Demetriades et al 9 2010 M 37 years 45 mm S, GK, S ×3 15 Gy 50% (max 30 Gy) 120 m 6 m
Puataweepong et al 10 2012 F 40 years 4.8 cm3 S, Linac, S 30 Gy in 6 hypo fractions 80% 72 m 3 m
Yanamadala et al 23 2013 F 51 years 18.5 cm3 S, GK, S ×3 14 Gy 50% (max 28 Gy) 59 m 11 m
Seferis et al 24 2014 F 54 years 3.5 cm3 S, GK, S 12 Gy 45% (max 26.7 Gy) 66 m F/U 6 m Alive reirradiation
Frischer et al 5 2018 NR NR NR GK, S ×2 13 Gy 50% (max 26 Gy) 96 m 9 m
Wolf et al 25 2018 NR NR NR S, GK, S 12 Gy (max 24.3 Gy) 104 m 24 m
Haq et al 11 2019 M 64 years NR S, GK, S ×2 10 Gy 50% (max 20 Gy) 122 m F/U 60 m Alive reirradiation
Peker et al 26 2019 F 40 years NR S, CK, S NR NR NR
Li et al 27 2021 F 53 years 40 mm S, S, GK, S NR 12 m 6 m
Li et al 27 2021 F 67 years 22 mm S, GK, S, GK, S NR 26 m F/U 40 m Alive reirradiation
Li et al 27 2021 F 32 years 60 mm S, GK, GK, S NR 20 m NR
De Jesus et al 2021 M 56 years 14.3 cm3 S, GK, S ×2 12 Gy 50% (max 24 Gy) 108 m 3 m Palliative

  • AVM, arteriovenous malformation; CK, cyber knife; Dx, diagnosis; F/U, follow-up up; GK, gamma knife; Max, maximum dose; MPNST, malignant peripheral nerve sheath tumour; NR, not reported; S, surgery; SRS, stereotactic radiosurgery.

Analysing our case and the 14 previously published cases of SRS-induced MPNST, there was a 77% female predominance (F:M 3.3:1), with a mean age of 51 (range: 32–81) at the time of the malignant transformation. The initial VS mean size was 39.4 mm on the largest dimension or 8.4 cm3. The mean marginal radiation dose was 13.0 Gy (12–17 Gy) with a mean maximal dose of 29.2 Gy (29–30 Gy). MPNST diagnosis was made at a mean time of 74 months after the SRS. The mean survival time after the MPNST diagnosis was 16 months. At the last follow-up, three patients were alive (6, 40 and 60 months).

MPNSTs of the eighth cranial nerve arising without prior irradiation are exceedingly rare, with an average incidence of 0.017 per 1 million persons per year.29 Seferis et al estimated that the 20-year risk of malignant transformation in a non-NF non-irradiated VS is 1.09–1.74 per 100 000, which increases to 15.6 per 100 000 for radiated cases.24 Frischer et al reported his long-term experience with GK for VS and identified only one case of a malignant transformation after GK SRS for an incidence of 0.2%.5 Patel and Chiang showed that the overall risk of developing an SRS-induced neoplasm after SRS to a VS was approximately 0.04% at 15 years with a malignant transformation of the VS or a radiation-induced malignancy arising from the surrounding normal tissue in the treatment field.21 In 2013, Hasegawa et al reviewed 440 patients with VS who received SRS followed for more than 10 years, and only one patient developed a malignant transformation for an annual incidence of malignant change of 0.02%.4 Nicolli and Ruckenstein did in 2015 a literature review of radiosurgical management of VS and showed an overall calculated risk for a malignant transformation between 0.03% and 0.3%.30 Wolf et al did a multicentre study in 2019 and identified only two cases in 3251 patients with benign tumours (0.06%) with a suspected malignant transformation after GK SRS, resulting in an incidence of 6.87 per 100 000 patient-years for a malignant transformation.25

After VS malignant transformation, multimodal therapy strategies including surgery, radiotherapy, and chemotherapy should be considered. The management of this tumour requires lifelong and regular MRI follow-up studies. For intracranial MPNSTs, radiotherapy seemed to provide a survival benefit regardless of surgical results; however, the extent of resection does not seem to significantly affect survival.14 27 Therefore, it is reasonable to advocate for a safe resection followed by adjuvant radiotherapy.

Learning points

  • Malignant peripheral nerve sheath tumour arising from benign vestibular schwannoma after stereotactic radiosurgery treatment is an uncommon but devastating complication.

  • The clinician and the patient need to understand the long-term radiation risks, specifically for malignant transformation of these lesions or radiation-induced malignancies.

  • Because of the low incidence of vestibular schwannoma transformation to a malignant peripheral nerve sheath tumour after radiotherapy in patients without neurofibromatosis, withholding treatment should not be recommended.

  • Patients with vestibular schwannomas treated with stereotactic radiosurgery need lifelong and regular MRI follow-up studies.

Ethics statements

Patient consent for publication

Footnotes

  • Contributors Manuscript conception was done by ODJ and JGSJ. Drafting the manuscript was done by ODJ, JGSJ, GSQ and RV. Review and approval of the final version was given by all the authors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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