A man in his late 60s with a history of Stage I melanoma of the upper thigh, for which he had undergone wide local excision and negative sentinel lymph node biopsy 2 years prior, presented with new metastatic disease. On imaging, he was found to have lesions of the lung, liver, vertebrae, and brain. Fine needle aspiration of a thoracic lymph node confirmed metastatic melanoma. Next generation sequencing was notable for BRAF V600E mutation.
The patient started treatment with combination ipilimumab and nivolumab. While undergoing immunotherapy, the patient also received radiation to his T7-T10 vertebral metastases (30 Gray (Gy) in 10 fractions) and had stereotactic radiosurgery (SRS) to 16 brain metastases. Spinal irradiation was performed with a 3D conformal technique using opposed anterior-posterior/ posterior-anterior fields. The maximum dose to the spinal canal was 33.5 Gy.
Magnetic resonance imaging (MRI) of the brain following SRS showed marked treatment response. Re-staging computed tomography (CT) of the chest, abdomen, and pelvis, performed 2 months after his initial staging scans, also showed major systemic response. Prior to starting his fourth cycle of ipilimumab and nivolumab, the patient noted the onset of intermittent numbness and tingling of the soles of his feet, with gradual ascension to his knees over the next 2 months.
MRI brain 1 month later showed a new punctate cerebellar metastasis, which was treated using SRS. Positron emission tomography (PET)/CT demonstrated resolution of numerous hyper-metabolic lesions with a remaining area of increased focal uptake in the left ischial tuberosity (Fig. 1). Given evidence of disease progression in the ischial tuberosity but not other systemic areas, the patient transitioned to pembrolizumab and received radiation to his ischial lesion. Approximately 2 weeks after starting pembrolizumab, the patient noted gait instability and ataxia, and further ascension of numbness to the level of his hips. At that time, he was still able to ambulate independently with the assistance of walking sticks. One month after starting pembrolizumab, the patient presented to the emergency department (ED) with 1 day of urinary retention and fecal incontinence. A spinal MRI was performed which showed T2 signal abnormality and patchy enhancement in the thoracic spinal cord (T5 to T10) concerning for myelitis or radiation necrosis without evidence of tumor or malignant cord compression. The T2 signal abnormality corresponded with the thoracic spinal radiation field (Fig. 2). Given that the lesion was enhancing and initially confined to the radiation field, radiation necrosis was favored at that time.
The patient’s immunotherapy was discontinued, steroids (dexamethasone 8 mg twice daily) were initiated, and two doses of bevacizumab (for possible radiation necrosis) were administered, without improvement. Lumbar puncture was deferred due to recent bevacizumab. Given the lack of improvement to optimal therapy for radiation necrosis, transverse myelitis was then favored. Results of serologic evaluation of metabolic (vitamin B12, thyroid stimulating hormone), infectious (human immunodeficiency virus, rapid plasma reagin), and autoimmune (anti-nuclear antibodies, anti-Ro/La, aquaporin-4 immunoglobulin G, erythrocyte sedimentation rate, C-reactive protein) etiologies of transverse myelitis were normal. The patient was trialed on high-dose intravenous methylprednisolone (1000 mg daily for 5 days) for transverse myelitis. His lower extremity numbness and gait instability progressed and he started plasmapheresis.
Following 15 sessions of plamapheresis, a dose of cyclophosphamide 1000 mg/m2 was added but the patient continued to decline with worsening urinary retention, bilateral lower extremity spasticity, and complete loss of lower extremity sensation to T5. He did not have upper extremity involvement. Cerebrospinal fluid (CSF) analysis at that time was remarkable for elevated protein (total protein, 99 mg/dL; institutional normal range, 15–45 mg/dL) and negative for malignant cells. Myelin basic protein was elevated at 31.6 ng/mL (normal < 5.5), and oligoclonal bands were matched in the serum and CSF, consistent with an ongoing systemic immune reaction. CSF albumin index was mildly elevated, suggestive of slight impairment of the blood-CSF barrier. Serum studies for antibodies to human T-lymphotropic virus (HTLV) I and II, and a paraneoplastic panel (anti-NR1, anti-GAD65, anti-alpha 3AChR, anti-LGI1, anti-VGCC, anti-VGKC, anti-CASPR2, anti-amphiphysin, anti-CV2, anti-Hu, anti-Ma, anti-Ta, anti-recoverin, anti-Ri, anti-Yo, anti-Zic4) were negative. A serum IL-6 level was normal. A serum TNF-alpha level was not obtained. MRI of the brain demonstrated two new intracranial metastases. MRI of the spine showed progression of transverse myelitis from T3 to T11 (Fig. 3c), now clearly outside the radiation field. Body PET/CT revealed worsening osseous metastatic lesions; therefore the patient began dabrafenib and trametinib. Given his ascending transverse myelitis despite optimal therapy other options including tocilizumab and infliximab were considered. Based on the low IL-6 level, the patient was started on infliximab. Spinal MRI 3 weeks after the first dose of infliximab showed a dramatic reduction of the level of the T2 cord signal abnormality back to T6 to T10 (Fig. 3d) with corresponding improvement in sensory level and muscle spasms. Continued treatment with infliximab led to additional incremental gains on imaging but without further clinical improvement. He subsequently developed systemic progression on dabrafenib and tremetinib (but with stable central nervous system disease) and ultimately succumbed to his disease.