Introduction
Retinoblastoma (Rb) is the most common intraocular malignancy in children worldwide and the most common intraocular malignancy across all ages in Jordan. Timely diagnosis and prompt management are critical for cure in these patients [1, 2]. The primary goal of Rb treatment is to cure the patient and secondarily to preserve the globe and vision when possible, ensuring this is safe. Rb is a complicated disease treated by different management modalities, including systemic chemotherapy, intra-arterial chemotherapy, intra-vitreal chemotherapy, and focal consolidation therapy [3–10]. Previous studies have shown that the cause of mortality in patients with Rb is related to metastatic disease [mainly to the central nervous system (CNS) or bone marrow], subsequent malignancies (seen especially in hereditary Rb survivors who received radiotherapy), and other non-tumor cause-specific mortality, including infections, endocrine and metabolic diseases, neurological diseases, circulatory diseases, and others [11–15].
Rb represents less than 4 % of all childhood malignancies. Rb incidence ranges from 1 in 18,000 to 30,000 live births [16]. Rb is most commonly diagnosed in the first two years of life, with the average age at diagnosis being around 18 months old [17].
Most patients present with leukocoria noticed by the caregiver. Other less common presentations include reduced vision, red uveitis like eye, buphthalmos, or proptosis.
Rb can be unilateral or bilateral, with bilateral disease most likely being hereditary.
In developed countries, Rb survival rates reach up to around 95% [18].
It is advised that patients with retinoblastoma be treated in a specialized center with general agreement that patients should be evaluated routinely, with 6 monthly ophthalmology exams, orbit, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and bone marrow biopsies [18]. Further relevant investigations according to the clinical presentation are recommended as well.
Herein, we present an unusual metastatic retinoblastoma to the intra-orbital optic nerve of the contralateral normal eye in a patient with unilateral retinoblastoma.
Case presentation
A 30-month-old female child presented in April 2016 with left leukocoria. The patient and her family were residing outside Jordan at that time, where she underwent examination under anesthesia showing total exudative retinal detachment, with a brain orbit MRI study showing a large left-sided intraocular mass, showing a hypointense signal on T2 weighted sequence with intermediate T1 signal intensity, mild post-contrast enhancement with retinal detachment (Fig. 1A) correlating with retinoblastoma, group D according to the International intraocular retinoblastoma classification (IIRC) [19].
Brain and orbit magnetic resonance imaging (MRI) was free of any extraocular tumor extension or brain metastasis at diagnosis. She underwent primary enucleation outside Jordan. The pathology report of the enucleated eye confirmed the clinical diagnosis of Rb with no high-risk pathological features i.e., there was no evidence of choroid invasion, optic nerve invasion, ciliary body invasion, or extra scleral extension. A month after enucleation, the patient and her family returned to Jordan, and her parents opted to consult the ocular oncology team at King Hussein cancer center (KHCC).
At KHCC, the patient underwent examination under anesthesia for the contralateral right orbit, which was normal. Paraffin blocks were not available for review by the pathologists at KHCC.
Orbit and brain MRI was repeated, with no evidence of left orbital tumor, CNS disease, and a normal right eye. Prosthesis fitting was provided (Fig. 1B). No adjuvant chemotherapy was offered. Six months later, the patient presented to KHCC with a lesion in the right contralateral parietal bone (Fig. 1C). MRI confirmed the presence of a right parietal osseous mass with accompanying soft tissue. No orbital recurrence, no contralateral orbital masses, or brain metastasis was seen. The osseous lesion was excised at KHCC, and pathology confirmed Rb metastasis.
The CSF biopsy was negative at that time; however, bilateral bone marrow biopsy showed metastatic disease, with 80–90% of tumor cells positive for synaptophysin and chromogranin. Subsequently, the slides and paraffin blocks of the left enucleated eye became available. A pathology review at KHCC confirmed the diagnosis. The focal choroidal invasion was identified, with a single focus less than 3 mm, without any other pathological high-risk features.
The patient received 4 cycles of systemic chemotherapy (cisplatin, cyclophosphamide, etopside), as per extra-ocular Rb protocol, which was completed in Jan 2017. She underwent an autologous bone marrow transplant (BMT) almost 10 months after enucleation in March 2017. This was followed by external beam radiation therapy (EBRT) to skull metastasis (EBRT as 25 Gy/10 fx to the pre-surgical volume) in May 2017.
The patient was kept on follow-up with routine clinical, ophthalmology examination under anesthesia, brain/orbit MRI and CSF and bone marrow biopsies every 6 months.
The patient was free of metastatic disease for almost 2 years. In April 2019, a month after the last free orbit and brain MRI, nearly one year after the BMT, three years after the initial diagnosis, the patient complained of a vision drop in the right eye from 20/20 to 20/50. Clinical examination showed right optic disk swelling (Fig. 1D) with no intraocular tumors. MRI showed diffuse thickening and contrast enhancement of the right intraorbital optic nerve in the previously normal eye (Fig. 2A, B). CSF biopsy did not show evidence of metastasis. The provisional clinical diagnosis was optic neuritis, given MRI findings and rapid vision loss. The patient was treated by intravenous pulse steroids for 3 days, 30 mg/kg. The visual acuity improved from 20/50 to 20/20. The patient was shifted to oral steroids. Unfortunately, 3 days after the oral steroids, her visual acuity dropped to counting fingers at 1 meter, without improvement in the severity of the optic disc edema.
The repeated MRI was stable as well.
The multidisciplinary ocular oncology team decided to consider the optic nerve enlargement as metastatic disease to the optic nerve. A repeat CSF biopsy was performed and showed only a few malignant cells. Chemoreduction with vincristine, carboplatin, and etoposide was initiated, but etoposide was unfortunately stopped due to an allergic reaction. This was followed by EBRT to the eye globe to save vision (EBRT as 20 Gy/10 fx). She showed a marked radiological response (Fig. 2CD), complete resolution of the optic disc edema, and improved visual acuity to 20/100.
Unfortunately, a few weeks later, she presented with lower limb weakness, as she could not walk. A whole spine MRI showed extensive diffuse leptomeningeal enhancement correlating with diffuse leptomeningeal metastasis (Fig. 2EF), and the CSF examination confirmed the diagnosis of CNS metastatic Rb. The patient passed away a few weeks later, and no autopsy was performed.
Discussion
Metastasis and extraocular spread are seen in up to 5% of Rb cases in the developed world.
Jubran et al. [20] suggested four patterns of extraocular disease, including metastasis to the central nervous, regional metastasis, and distant metastasis, in addition to trilateral retinoblastoma. The central nervous system is the most common site of metastasis [21].
Bone marrow metastasis is also common. Extraocular or metastatic retinoblastoma has a poor prognosis [17].
A few reported cases of retinoblastoma metastasizing to unusual sites such as the parotid gland [17] or long bone [18]. Mohan et al. reported a case of retinoblastoma metastasizing to the contralateral bony orbit involving the maxillary sinus with orbital floor involvement [22].
To the best of our knowledge, no prior case of Rb with isolated metastasis to the contralateral optic nerve has been reported in the literature.
In the adult population, optic nerve metastasis can be seen in breast and lung cancer [23].
In pediatrics, optic nerve metastasis is rare, with only a few reported cases.
Kim et al. reported isolated optic nerve infiltration in a girl with prior history of non-Hodgkin’s lymphoma [24].
Garrity et al., reported a case of posterior fossa medulloblastoma with biopsy-proven metastasis to the optic nerve 28 months after surgery, chemotherapy, and craniospinal irradiation [25]. Hurtle et al., reported a pineoblastoma metastasizing to the optic nerve in a 10-year-old girl two years after primary cancer treatment [26].
Tumors arising from the optic nerve itself are uncommon. Optic nerve glioma, which causes fusiform thickening of the optic nerve, is the most common primary tumor of the optic nerve, which may or may not show contrast enchantment and is commonly associated with neurofibromatosis type 1 (optic pathway gliomas) [27]. Optic nerve meningioma usually extends from intracranial meningioma through the optic canal [27]. Optic nerve sheath meningioma is a different entity, with only 2–4% reported in pediatric patients [28]. Both conditions, optic nerve glioma and meningioma, have indolent clinical course.
Patients with hematolymphoid malignancies, including lymphoma and leukemia, may have orbital and/or optic nerve infiltration. The confirmed diagnosis, proper lab investigations, CSF, and bone marrow biopsies are important clues to the diagnosis. MRI offers helpful diagnostic features showing hypointense T2 signal and diffusion restriction with the hypointense signal on the apparent diffusion coefficient map (ADC map).
Non-tumoural lesions of the optic nerve include inflammatory causes such as optic neuritis.
The appearance of the right optic nerve in our patient was presumed to be inflammatory, representing optic neuritis, given rapid vision loss and MRI appearance.
Optic neuritis is uncommon in pediatrics, usually linked to viral illness or vaccination [29].
It presents with rapid vision loss, which tends to be more severe than in adulthood, pain during eye movement, and the appearance of the optic nerve head on ophthalmoscopy.
Treatment is usually indicated in bilateral cases with severe loss of visual acuity. Unilateral cases and less severe cases can be observed and followed up [30]. Brain MRI in patients with optic neuritis is advised in the first 2 weeks to assess for the possible manifestation of multiple sclerosis [29]. Re-assessment of any atypical or irresponsive cases is mandatory [31].
Optic neuritis is expected to respond to steroid treatment, with faster recovery in patients undergoing IV steroids; however, no such studies in the pediatric population are available [32].
Our patient’s lack of response to treatment was worrisome, and the metastatic process was considered based on clinical suspicion. A repeat CSF analysis is recommended to increase sensitivity [33]. In our patient’s case, the repeat CSF showed only a few malignant cells. Recent data from China shows that retinoblastoma with CNS metastasis carries a poor prognosis with a median survival of 6 months [33]. Although advances in the management of retinoblastoma treatment have improved the overall prognosis in children with the disease, metastatic disease is still seen, particularly in developing countries. A high index of suspicion for metastasis, especially in developing countries, should be kept in mind. Patients presenting with a new complaint should be thoroughly investigated.
Conclusion
Retinoblastoma metastasis to the contralateral optic nerve has not been previously reported. Patients with retinoblastoma presenting with new symptoms should be investigated thoroughly. Unusual metastasis of retinoblastoma can be seen with increased patient survival. A negative CSF analysis does not rule out CNS metastasis; repeat CSF is advised if high clinical suspicion exists.
Conflict of interest
None declared.
Funding
None.