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Superior oblique myositis following targeted therapy for papillary thyroid carcinoma

Published:February 16, 2021DOI:https://doi.org/10.1016/j.jcjo.2021.01.016
      Papillary carcinoma of the thyroid gland (PCTG) constitutes 80%–85% of thyroid cancers globally. Despite early lymphatic invasion, PCTG has a relatively indolent course and rarely metastasizes outside of the neck.
      • Gallagher RJ
      • Liverman CS
      • Arnold PM.
      Papillary thyroid adenocarcinoma with occipital lobe metastasis 48 years after original diagnosis: case report.
      Metastasis to the brain from PCTG is even more uncommon and usually occurs in the context of widely disseminated disease. While the mainstay of treatment for intracranial metastasis from PCTG includes surgical excision and radiotherapy, recent advances into our understanding of the molecular pathways governing PCTG have facilitated development of novel targeted chemotherapeutics. We present a case of superior oblique myositis that was presumed secondary to treatment of widely metastatic PCTG with dabrafenib and trametinib therapy. To our knowledge this is the first such case in the English language ophthalmic literature.

      Case

      A 61-year-old man presented with subacute, progressive, right-sided peripheral vision loss preceded by a month of headaches, 2 episodes of right-sided scintillating scotomas, and a single episode of transient confusion. Past medical history was significant for PCTG treated with total thyroidectomy, bilateral paratracheal, and lateral compartment neck dissection, followed by radioactive iodine therapy. Initial evaluation revealed 20/20 visual acuity in both eyes (OU) and a right homonymous hemianopsia. Computed tomography (CT) scan of the brain showed vasogenic edema and a mass in the left parieto-occipital lobe. Magnetic resonance imaging (MRI) showed multifocal brain metastasis, including left parietal-occipital lesion. CT scan of the chest and abdomen revealed metastatic involvement of the lungs, hilar and mediastinal lymph nodes, kidneys, and liver. The patient was treated with oral prednisone and levetiracetam. After surgical resection the patient was treated with 10 rounds of whole brain radiotherapy followed by a single round of stereotactic radiosurgery to the residual left parietal-occipital lesion. BRAF V600E testing confirmed the mutation, and the patient was treated with 300 mg/day of dabrafenib and 2 mg/day of trametinib. The trametinib dosage was subsequently reduced to 150 mg/day owing to nausea and vomiting.
      Eight months after his initial presentation, the patient endured 3 weeks of right frontal headache and new binocular vertical diplopia. On examination, visual acuity had decreased to 20/50 in the left eye (OS). There was a left hypertropia of 15 prism diopters OS. Cerebrospinal fluid analysis was unremarkable with normal glucose, protein, leukocyte count, and negative malignant cells on cytology. Repeat CT scan of the head showed stable intracranial lesions. MRI of the brain and orbits revealed enhancement of the left superior oblique muscle and surrounding soft tissue (Figs. 1A and 1B). Owing to concerns for a superior oblique myositis secondary to dabrafenib and trametinib therapy, the patient was treated with a reduced dosage of these medications and initiated on a 30-day oral prednisone taper, which resolved the symptoms.
      Fig 1
      Fig. 1Gadolinium-enhanced T1-weighted fat-suppressed coronal MRI images demonstrating enhancement of the left superior oblique muscle (A, yellow arrow) and anterior left superior orbital soft tissue (B, blue arrow). Repeat imaging at a 2-month interval demonstrated resolution of the left superior oblique muscle enhancement (C, green arrow).
      At a subsequent 2-month follow-up, the patient reported interval resolution of his right frontal headache and vertical diplopia. Unfortunately, the vertical diplopia recurred 1 week before the follow-up examination, coinciding with weaning of his prednisone therapy. His prednisone was increased and reweaned without recurrence of symptoms. Repeat MRI of the brain and orbits revealed decreased enhancement of the left distal superior oblique muscle in comparison with prior imaging (Fig. 1C).

      Discussion

      Thyroid cancer accounts for 1% of malignancies globally. PCTG is classified as a form of differentiated cancer that arises from thyroid follicular cells. The standard therapeutic approach to PCTG involves surgical resection followed by radioactive iodine ablation. Owing to the indolent course of PCTG and a high response rate to treatment, the prognosis for PCTG is excellent, with a 95% 5-year survival rate. Unfortunately, between 4%–15% of PCTGs remain resistant to standard treatment and metastasize to distant sites.
      • Gallagher RJ
      • Liverman CS
      • Arnold PM.
      Papillary thyroid adenocarcinoma with occipital lobe metastasis 48 years after original diagnosis: case report.
      These aggressive PCTGs have a comparatively poor prognosis, necessitating the development of effective salvage therapies. Several novel therapeutics have been recently approved for treatment of aggressive PCTGs and are generally classified into 2 categories: small molecule-kinase inhibitors and immunotherapy.
      • Naoum GE
      • Morkos M
      • Kim B
      • Arafat W.
      Novel targeted therapies and immunotherapy for advanced thyroid cancers.
      Small-molecule kinase inhibitors are directed against intracellular signalling pathways that control cellular survival, proliferation, and differentiation, whereas cancer immunotherapies enhance the body's immune response against malignant cells.
      Multitargeted kinase inhibitors (MKIs) are a class of small-molecular kinase inhibitors that target different components of the mitogen-activated protein kinase (MAPK) signalling pathway. One such MKI, dabrafenib, targets B-Raf and was initially developed for use in aggressive melanomas. Dabrafenib is often combined with an inhibitor of the downstream kinase MEK, trametinib. This combination therapy has recently been approved for advanced thyroid cancers, as 30%–70% of PCTGs contain activating BRAF mutations, most commonly V600E (a substitution of glutamic acid for valine at amino acid 600), leading to dysregulation of MAPK signaling.
      • Naoum GE
      • Morkos M
      • Kim B
      • Arafat W.
      Novel targeted therapies and immunotherapy for advanced thyroid cancers.
      Unfortunately, widespread use of MKI therapy is hampered by a high frequency of treatment-related adverse events (AEs).
      The most common AEs associated with dabrafenib and trametinib combination therapy are dermatitis, pyrexia, arthralgia, fatigue, diarrhea, and vomiting. Several studies have also found high rates of ocular AEs with B-Raf and MEK inhibitors. B-Raf inhibitors, such as dabrafenib, are thought to disrupt ocular immune privilege, leading to uveitis, iritis, optic neuritis, and vitritis.
      • Stjepanovic N
      • Velazquez-Martin JP
      • Bedard PL.
      Ocular toxicities of MEK inhibitors and other targeted therapies.
      In contrast, MEK inhibitor–associated AEs arise through direct disruption MAPK signalling in various cellular compartments of the eye, leading to central serous chorioretinopathy, retinitis pigmentosa, and retinal venous occlusion.
      • Stjepanovic N
      • Velazquez-Martin JP
      • Bedard PL.
      Ocular toxicities of MEK inhibitors and other targeted therapies.
      A review of the literature for MKIs causing myositis yielded only 3 previously reported cases, detailed further in Table 1.
      • Harrison SR
      • Tew A
      • Steven N
      • Fisher BA.
      Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy.
      • van Landingham SW
      • Puccetti D
      • Potter H
      • Gamm D
      • Diamond EL
      • Lucarelli MJ.
      Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.
      • Karsan N
      • Barker R
      • Wren D.
      Myositis and metastatic melanoma.
      Of these, only 1 case involved an extraocular muscle, with the patient developing an acute necrotizing lateral rectus myositis 4 weeks after being started on dabrafenib for Langerhans cell histiocytosis.
      Table 1Previously reported cases of MKIs causing myositis
      AuthorJournalYearPatient DetailsCancer TypeTargeted TherapyComplicationManagement of ComplicationOutcomeTargeted Therapy Stopped?
      Harrison et al.
      • Harrison SR
      • Tew A
      • Steven N
      • Fisher BA.
      Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy.
      Rheumatology201881 y/o FMetastatic melanomaDabrafenib and trametinibDermatomyositisPrednisone, IVIGDeclined further therapy for melanomaYes
      van Landingham et al.
      • van Landingham SW
      • Puccetti D
      • Potter H
      • Gamm D
      • Diamond EL
      • Lucarelli MJ.
      Necrotizing myositis in a rectus muscle arising in the setting of long-standing Langerhans cell histiocystosis and recent dabrafenib treatment.
      Oncologist202018 y/o MLangerhans cell histiocytosisDabrafenibLateral rectus necrotizing myositisMonitoredNo recurrenceYes
      Karsan et al.
      • Karsan N
      • Barker R
      • Wren D.
      Myositis and metastatic melanoma.
      Clinical medicine201570 y/o MMetastatic melanomaVemurafenibBell's palsy, rhabdomyolysisMonitoredAbnormalities resolved after therapy cessationYes
      MKI, multitargeted kinase inhibitors; M, male; IVIG, intravenous immunoglobulin.
      Furthermore, the systemic and ocular toxicities arising from MKIs and immunotherapy are managed similarly. Mild toxicities can be managed expectantly, whereas more severe effects require dose reduction or discontinuation with concomitant glucocorticoids therapy. Ultimately, clinicians should be aware of the pleomorphic presentations of MKI-associated AEs.

      Footnotes and Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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