Radiation-induced glioblastoma of the conus medullaris from radiation treatment of cervical cancer

Abstract

Radiation-induced spinal glioblastoma is an extremely rare disease with only four previously published reports in the literature. We report the fifth case, a 69-year-old woman who previously underwent treatment with brachytherapy for cervical cancer, and thereafter presented with neurologic deficits from a conus medullaris tumour. Biopsy and histopathology confirm glioblastoma, not otherwise specified. Treatment of spinal glioblastoma consists of surgery, either biopsy or excision and chemoradiation. However, results are still unsatisfactory and prognosis remains poor.

Background

Spinal glioblastoma is a rare disease with an incidence of 0.12 per 100 000 individuals.¹ Most of these cases are primary tumours and there are only about 200 cases reported in the literature.^{1 2} Secondary radiation-induced glioblastomas occur even less frequently and usually arise intracranially.³ For those that arise in the spinal cord, there have only been four previously reported cases, and none of which occured in the conus medullaris nor have come from a history of brachytherapy for cervical cancer.^3–6 Because of the long latency for diagnosing radiation-induced tumours, it is of importance to keep these in mind in patients presenting with tumours distant from but still within the previous irradiation field.⁷

Case presentation

This is a case of a 69-year-old woman who presented in March 2020 with a 3-month history of rapidly progressive bilateral lower extremity weakness and incontinence. She had previously been treated for cervical squamous cell carcinoma 15 years prior, having undergone total hysterectomy with bilateral salpingo-oopherectomy, chemotherapy and brachytherapy. She had no recurrence of cervical cancer. On consult, she had 2/5 strength in her bilateral lower extremities, with numbness and paresthesia. She also reported urinary incontinence and constipation, necessitating an in-dwelling catheter. She also noted low back pain radiating to both legs. Investigations revealed an intramedullary conus medullaris tumour causing her symptoms and she was advised surgery because her symptoms were more of myelopathy than radiculopathy. Because of the lockdowns imposed due to COVID-19, she underwent surgery 2 weeks after consult, and by that time, she was already paraplegic and bed-bound.

Investigations

A lumbosacral MRI with gadolinium was done revealing a 3.3×1.2×1.1 cm, T1 hypointense, T2 mildly hyperintense, diffusely contrast enhancing intramedullary tumour expanding the conus medullaris at the level of L1. A disc bulge at L4–L5 and an old fracture at L5 with stable spondylolisthesis was also seen (see figure 1).

Figure 1.

(Coloured) Lumbosacral MRI with gadolinium, sagittal (A–C) and axial (D) cuts: 3.3×1.2 x 1.1 cm, T1 hypointense (A), T2 mildly hyperintense (B), diffuse contrast enhancing (C and D) intramedullary tumour expanding the conus medullaris. Disc bulge at L4-L5 with old fracture of L5 and stable spondylolisthesis is also seen.

Differential diagnosis

Differential diagnoses for an intramedullary lesion of the conus medullaris include ependymoma, gliomas and glioblastoma both primary and secondary. Ependymomas are the most common of these and can arise in the filum terminale or the conus medullaris. Although rare, given the age and history of cancer in this patient, metastases can also be considered. Regardless, diagnosis is mainly histopathologic, highlighting the importance of a tissue specimen to guide treatment after surgery.

Treatment

She underwent L1 decompressive laminectomy, biopsy with debulking of tumour. Intraoperatively, the surgeon noted pale grey-yellow soft intramedullary tumour that was expanding the conus medullaris, with areas of liquefactive necrosis and fibrosis. Histopathology revealed glioblastoma, not otherwise specified, showing hypercellular sheets of neoplastic astrocytes with prominent microvascular proliferation and tumour necrosis. Immunohistochemistry was positive for glial fibrillary acidic protein (GFAP) and did not exhibit reactivity to isocitrate dehydrogenase 1 (IDH1), cellular adhesion molecule (CAM) 5.2 and pancytokeratin (see figure 2).

Figure 2.

(Coloured) Histopathologic examination of the tumour. H&E staining on low (A) and high (B) power showing hypercellular sheets of neoplastic astrocytes with prominent microvascular proliferation and tumour necrosis; moderate to severe nuclear atypia and brisk mitotic activity are also noted (B). Immunohistochemistry study for GFAP highlighted the delicate astrocytic processes (C). The tumour cells did not exhibit IDH1, CAM5.2 and pancytokeratin immunoreactivity (D–F).

Outcome and follow-up

She is 4 months after surgery as of this writing. After confirmation of the histopathology of her biopsy, she was advised adjuvant radiotherapy and chemotherapy with temozolamide. A family conference was done and main points rested on weighing the cost of treatment to disease prognosis. She has decided not to pursue further treatment and instead focus on improving quality of life and symptomatology. She is still paraplegic, incontinent and bed-bound.

Discussion

The criteria for the diagnosis of radiation-induced malignancy include (1) the new tumour must be histologically distinct from the original tumour, (2) the new tumour must be in the irradiated field, (3) there must be a relatively long asymptomatic period after irradiation and the clinical appearance of the new tumour (the so-called 5-year-cure period) and (4) the new tumour must be proven to exist histopathologically.⁷ Our case has all the diagnostic criteria to for secondary radiation-induced malignancy. The tumour is also negative for immunohistochemistry for IDH, supporting its de novo occurrence rather than malignant degeneration from pre-existing low-grade glioma.⁸

Although indeed rare, many of the reports on radiation-induced gliomas included those that were WHO grade II and III tumours and did not specifically state glioblastoma.^9–12 We included only in this review, those four studies in which a specific diagnosis of radiation-induced glioblastoma was made and treated as such.^3–6

Clifton⁴ in 1980 originally reported a case of a 21-year-old man who initially underwent radiation for a mediastinal Hodgkin’s lymphoma and developed radiation-induced glioblastoma in the cervicothoracic region after 6 years. There was worsening neurological symptomatology over 4 months. He underwent decompressive laminectomy and biopsy under an emergent basis because of deteriorating neurologic condition. Intraoperative findings showed a tense flattened discoloured cord, with cystic necrosis that was evacuated to relief of pressure. This patient did not improve postoperatively and did not receive any adjuvant treatment. He subsequently succumbed to pneumonia 10 weeks after surgery.

Ng and colleagues⁵ reported on a 26-year-old man who underwent mediastinal radiotherapy for Hodgkin’s lymphoma. Latency period to the radiation-induced glioblastoma was 2 years. Worsening neurologic function was observed for a period of 2 months. MRI revealed expansion of the cord secondary to a mass from T9 to T12, causing a syrinx proximally. He underwent T10–T11 laminectomy and biopsy of the tumour. Intraoperatively, they noted the tumour to be deep within the substance of the cord with no exophytic component. He did not improve after surgery and underwent adjuvant radiotherapy to the thoracic spine and oral temozolamide. He went back to his home country after treatment and expired after a few weeks likely due to pneumonia and disease progression.

Ahn and Kim³ described a case of a 17-year-old woman who had underwent radiation from the zygomatic to C6 regions for embryonal nasopharyngeal rhabdomyosarcoma. She presented with neurological symptoms after a latency of 13 years, revealing enlargement of the cervical cord from C2 to C4 due to an intramedullary tumour on MRI. C2–C4 laminectomy with biopsy was performed. Intraoperatively they noted the cervical cord to be diffusely enlarged with the tumour to be barely distinguishable from normal cord tissue. The patient had postoperative deterioration secondary to oedema of the postoperative site, necessitating reoperation with additional laminectomy and debulking of the tumour. Adjuvant chemoradiation was done for the patient and was still alive at the writing of their report for a survival of 7 months.

The most recent report of radiation-induced spinal cord glioblastoma was by Kikkawa and colleagues⁶. They described a case of a 21-year-old man with T-cell lymphoblastic lymphoma who underwent irradiation of the mediastinal region. He developed neurologic symptoms after 10 years, with workup revealing an intramedullary tumour from C6 to T6, with enhancement of the surface of the cord and dura, suggesting cerbrospinal fluid dissemination of disease. This patient refused spinal surgery, but had a lumbar puncture done, which showed atypical cells that were positive for Olig-2. Interestingly, this patient had a right frontal periventricular lesion, for which he had stereotactic biopsy done revealing glioblastoma. Postbiopsy, he underwent adjuvant chemoradiotherapy with temozolamide and whole brain and spine radiotherapy, with boosts to the identified lesions on MRI. The patient was still alive at 9 months of follow-up as of the time of writing of their paper, with no deterioration of neurologic status.

In our review of cases, two of the cases came from radiation for Hodgkin’s disease, one from nasopharyngeal embryonal rhabdomyosarcoma and one from lymphoblastic lymphoma. Our case is the first reported radiation-induced spinal glioblastoma from brachytherapy from treatment of cervical cancer. Although all patients had surgery, one case had cranial surgery and not spine surgery.⁶ Surgery was mainly for decompression in spine cases and histologic diagnosis. The mean latency period for all cases, including ours, was 9.2 years. Our case had the longest latency period of 15 years. Of the five cases, two patients died at the time of the reports, both from respiratory complications likely owing to the location of their disease.^{4 5} Only one patient did not receive any adjuvant treatment.⁴

The treatment of radiation-induced spinal glioblastoma mirrors treatment for primary spinal glioblastoma.^{3 5 6} No consensus as to appropriate surgical treatment, gross total resection versus subtotal resection versus biopsy, has been made; and most institutions would still opt for adjuvant chemoradiation with temozolamide in the treatment of spinal glioblastoma.¹³ As such, the benefits of these treatment modalities are still not clear. An analysis of the National Cancer Registry in 2018 by Moinuddin and colleagues found that surgery with adjuvant therapy did not confer any overall survival benefit compared with chemoradiation alone and may even be associated with more morbidity because of the infiltrative nature of the disease.¹⁴ This effect is confirmed by Liu and colleagues, although they argue that postoperative radiotherapy is associated with improved survival, reducing the HR by 46%.¹⁵ There is also still no consensus as to whole brain or spine or targeted radiotherapy as the method of choice, but the safety threshold of 5000–5500 Gy of the spinal cord must be kept in mind.¹ For chemotherapy, there have been reports on the use of Bevacizumab in lieu of temozolamide particularly in recurrent cases.¹⁶ Bevacizumab is preferred because it reduces mass effect and peritumoral oedema.¹⁷ There is still no unified treatment paradigm for spinal cord glioblastomas, and due to its rarity, there will not likely be any randomised control trials to prove such.¹⁸ This would much be more true in the case of radiation-induced spinal gliobastomas.^{4 5} However the case, patients with spinal cord glioblastoma still have a uniformly poor prognosis with overall survival rates of 3–21 months.1 2 14 17

Learning points.

• This is the fifth reported case of a radiation-induced spinal glioblastoma and the first from a patient with a history of cervical cancer.

• Because of the long latency for diagnosis of radiation-induced tumours, including spinal glioblastoma, this differential should always be considered in cases with a history of radiation treatment for cancer.

• Imaging is of an intramedullary tumour, diagnosis is mainly histopathologic showing the glioblastoma and should follow clinicopathological criteria for radiation-induced malignancy.

• Because of the scarcity of reported cases, management consists of surgery with adjuvant chemoradiotherapy and mirrors management of primary spinal glioblastoma.