Clinical ophthalmologic and radiologic features

Three patients presented with the chief complaint of leukocoria and two patients with eyelid swelling. Two patients had bilateral RB and three patients had unilateral RB. B-mode ultrasonography of all patients showed solid tumor masses, but there was no obvious invasion of the ON (Fig. 1). All five patients underwent whole-body CT and head MRI imaging as the initial radiologic investigation at the NCCHD before treatment. CT did not detect ON invasion in two patients, whereas MRI showed ON invasion in all patients (Figs. 2 and 3). Cerebrospinal fluid (CSF) cytology was performed for all patients before or during treatment. Bone marrow biopsy was done for four patients (cases 2–5) before treatment. Case 2 showed CSF positivity before treatment, and case 4 showed CSF positivity after enucleation. The bone marrow biopsies were all negative.

Fig. 1

B-mode ultrasonograms of cases 1–5 (a-e). A solid tumor mass with highly reflective foci is seen in each case, but no obvious invasion of the optic nerve (ON) is detected in any case

Fig. 2

Contrast-enhanced computed tomography (CT) images of Cases 1–5 (a-e). ON swelling and contrast enhancement indicating ON invasion (arrows) are seen. There is no evidence of ON invasion (c, e)

Fig. 3

Contrast magnetic resonance imaging (MRI) images of case 1–4 (a-d) and MRI SPACE image of case 5 (e). ON contrast enhancement shows ON invasion (arrows). An enlarged origin of the left ON with disruption of the surrounding subarachnoid space indicates ON invasion (arrowhead)

The pre-treatment findings in the five cases are summarized in Table 1. The specific clinical courses and radiologic features of the five cases are provided below.

Table 1 Pre-treatment findingsCase 1

An 18-month-old female infant with leukocoria OS was referred to our center with suspected bilateral RB. At the initial examination, anisocoria was observed and the left eye showed mydriasis and leukocoria. Ophthalmoscopy showed that the RB extended from the inferior to nasal retina, but the macula was not involved in the right eye. In the left eye, the RB extended throughout the fundus. B-mode ultrasonography showed a large solid mass with highly reflective foci OS (Fig. 1a) and a small mass OD. There was no obvious ON invasion on ultrasonography. The right eye was classified in Group D and the left eye in Group E of the International Classification of Retinoblastoma (ICRB) [10]. CSF cytology was negative before treatment. A bone marrow biopsy was not performed in this case.

Brain CT showed an intraocular tumor with bilateral calcification. The left ON was thicker than the right and showed contrast enhancement (Fig. 2a). On MRI, the left ON showed contrast enhancement and swelling, and the RB infiltrated the ON by 13 mm, which is in front of the optic canal on imaging. There was no obvious invasion in the right ON (Fig. 3a).

Case 2

A 15-month-old male infant with swelling of the left upper eyelid was referred to the NCCHD with suspected RB OS. At the initial examination, the left eye showed leukocoria. The fundus of the left eye was not visible. The right eye was normal. B-mode ultrasonography showed a large solid mass OS (Fig. 1b). The ON invasion was not obvious on ultrasonography.

CT showed an intraocular tumor OS. The left ON was obviously thicker than the right and showed contrast enhancement that continued intracranially (Fig. 2b). MRI showed the contrast effect in the left ON with 31 mm of infiltration to just in front of the intracranial optic chiasm (Fig. 3b). A biopsy performed to rule out an ON glioma and hamartoma identified RB. We performed lensectomy and vitrectomy using the limbal approach. Specimens were obtained from the tumor mass. Considering the possibility of surgical dissemination, the patient underwent transcorneal surgery without vascular structures. The left eye was classified in Group E of the ICRB. CSF cytology was positive before treatment and a bone marrow biopsy was negative.

Case 3

A 21-month-old female infant with eyelid swelling of her right upper eyelid was referred to our center. The anterior segment OD showed inflammation, iris rubeosis, and synechia. During the fundus examination, the right eye could not be evaluated because of vitreous opacity and the left eye was normal. B-mode ultrasonography showed a solid mass with highly reflective foci OD (Fig. 1c). No ON invasion was obvious on B-mode ultrasonography. The right eye was classified in Group E of the ICRB. CSF cytology and bone marrow biopsy were negative before treatment.

On CT, an intraocular tumor with contrast enhancement and calcification was seen OD. The right ON has no contrast enhancement or swelling (Fig. 2c). MRI showed contrast enhancement of the right ON and posterior wall of the right eye, with infiltration to 3 mm of the anterior end of the ON (Fig. 3c).

Case 4

A 22-month-old male infant with leukocoria OD was referred to our center. The examination showed corneal edema and iris rubeosis OD. The fundus of the right eye could not be visualized. The fundus of the left eye was normal. B-mode ultrasonography showed a mass with a highly reflective area OD (Fig. 1d). No ON invasion was obvious on B-mode ultrasonography. The right eye was classified in Group E of the ICRB. CSF cytology was negative initially and became positive after enucleation. A bone marrow biopsy was negative.

CT showed an intraocular tumor with contrast enhancement and calcification OD. The right ON was thicker than the left and showed a contrast effect (Fig. 2d). MRI showed contrast enhancement of the right ON with infiltration of 19 mm in front of the optic canal in the orbit (Fig. 3d).

Case 5

A 3-month-old male infant with leukocoria OS was referred to our center. At the examination, the tumor touched the posterior lens capsule. Fundus examination showed RBs on both fundi. Small tumors were scattered through the right fundus, but the macula was intact. The left fundus was covered by tumor. Fluorescein angiography showed five small tumors on the right fundus. B-mode ultrasonography showed a large mass with a highly reflective area OS (Fig. 1e), but it could not detect a tumor mass OD. The right eye was classified in Group A and the left eye in Group E of the ICRB. CSF cytology and bone marrow biopsy were negative before treatment.

CT showed an intraocular tumor with calcification OS, but no obvious tumor was detected OD. A contrast effect and swelling were not detected in either ON (Fig. 2e). An MRI sampling perfection with application-optimized contrasts using different flip angle evolutions (SPACE) image showed that the origin of the left ON was enlarged with disruption of the surrounding subarachnoid space. RB infiltration of 5 mm into the anterior end of the left ON was observed (Fig. 3e).

Primary treatment

Basically, we try to perform neoadjuvant chemotherapy in cases with ON invasion and then perform secondary enucleation when MRI no longer shows ON invasion. However, case 1 had presented before this strategy was established and was preceded by enucleation. Four patients (cases 2–5) underwent chemotherapy as the primary treatment. Three of four patients (cases 3–5), who primarily underwent chemotherapy ultimately underwent enucleation, while one patient (case 2) could not undergo enucleation due to consistent ON invasion seen on MRI, positive results of CSF, and progression of liver metastasis. Case 5 with bilateral RB underwent photocoagulation for small tumors of the right fundus; enucleation was not planned for this eye.

The chemotherapy regimens differed in each case. At NCCHD, the regimens for RB with ON invasion are basically the same as those for medulloblastoma [11,12,13]. Intrathecal injection (IT) also was basically used according to these regimens, but in some cases, IT was performed at the same time as the CSF examination to determine the efficacy of treatment for positive CSF status. The treatments of the five cases are summarized in Tables 2 and 3.

Table 2 Treatment of 5 casesSurgical treatment

Of the patients who underwent enucleation, the ON surgical margin was positive in case 1, which preceded enucleation. In cases 3–5, we checked for the absence of ON invasion on MRI after neoadjuvant chemotherapy and then performed enucleation. The ON surgical margins were negative in all of them. Case 5 underwent enucleation using a double approach [8] that included both the anterior and neurosurgical approaches to ensure that ON surgical margins were negative.

Histopathologic results

All enucleated eyes were examined pathologically. In case 1, the tumor cells were continuously infiltrating beyond the cribriform plate to the surgical margin (Fig. 4a). Tumor cells were observed in the epidural tissue (Fig. 4b). In case 2, the biopsy established a diagnosis of RB, and small round cells formed a small cluster. In case 3, the ON showed fibrotic changes due to neoadjuvant chemotherapy. No viable tumor cells were seen in the surgical margin (Fig. 4c) or arachnoid space, while there were tumor cells in the ON and rosettes within the choroid (Fig. 4d). In case 4, the ON showed fibrotic changes due to neoadjuvant chemotherapy. No viable tumor cells were seen in the surgical margin (Fig. 4e), ON, or arachnoid space (Fig. 4f). In case 5, no viable tumor cells were seen in the ON, surgical margin (Fig. 4g), or arachnoid space. The ON was retracted into the eye due to neoadjuvant chemotherapy (Fig. 4h).

Fig. 4

Histopathological images of case 1 (a, b), case3 (c, d), case 4 (e, f) and case 5 (g, h). a ON with tumor invasion. Tumor cells observed in epidural tissue (box). Hematoxylin and Eosin (H&E) staining. Bar = 500 μm. b Tumor cells in epidural tissue. H&E staining. Bar = 50 μm. c No viable tumor cells are seen in the surgical margin. H&E staining. Bar = 200 μm. d ON showed fibrotic changes. Tumor cells found in the ON (arrow) and the choroid (arrowhead). H&E staining. Bar = 500 μm. e No viable tumor cells are seen in the surgical margin. H&E staining. Bar = 200 μm. f ON with fibrotic change. H&E staining. Bar = 500 μm. g ON with negative surgical margin. H&E staining. Bar = 200 μm. h ON retracted into the eye. Arachnoid space and ON without viable cells. H&E staining. Bar = 500 μm

Adjuvant treatment

All enucleated patients underwent chemotherapy postoperatively based on a high-risk preoperative evaluation that there was ON invasion. High-dose chemotherapy was administered to the cases with a positive ON margin or positive CSF. Case 1 had a positive ON surgical margin, and case 4 had a positive CSF after enucleation. When high-dose chemotherapy was administered, autologous bone marrow transplantation or autologous peripheral blood stem cell transplantation was performed.

Radiotherapy

Cases 1-4 were treated with radiotherapy (total dose of external beam radiotherapy, 40–45 Gy). Radiotherapy was administered to the orbit whenever the disease was contained within the orbit and to the whole brain and spinal cord if dissemination to the CSF had occurred. Radiotherapy was administered to distant metastases (the liver in case 2).

Case 5 with bilateral RB did not undergo radiotherapy; MRI was performed and showed 5 mm of ON invasion and the patient achieved a negative surgical margin and no residual viable tumor cells in the pathological findings. The patient was younger than 1 year and had bilateral RB that seemed to have a germline mutation. Therefore, case 5 was at high risk for a secondary cancer.

Treatment-related toxicity

Late complications included central endocrine abnormalities and cataracts due to radiotherapy in cases 1 and 4. Neurologic symptoms due to multiple cerebral infarctions and hemorrhage developed in case 2. No relapse or second cancer occurred in any cases.

Prognoses

Four patients were alive at the last follow-up. Case 2, which had intracranial invasion seen at the initial diagnosis, died 11 months after the initial diagnosis (Table 2).