Neuroblastoma is the most common extracranial solid tumor in children, and 20% to 30% of pediatric patients present with orbital manifestations.1,2 Orbital findings usually represent metastases to periocular bony structures and the central nervous system, including proptosis, periorbital ecchymosis,2–4 ptosis and Horner syndrome,3–5 opsoclonus/myoclonus,6 blindness, and heterochromia iridis.3–5 Primary orbital neuroblastoma is documented to be rare and its origin is not clear.4,7 Apart from its main ophthalmic presentation due to orbital metastasis, intraocular structures (mainly the iris) may also be affected by the tumor. However, involvement of the neuroblastoma is extremely rare in the literature.8–10
We aimed to present a histologically proven neuroblastoma of the iris in a 2-month-old infant. The iris lesion was detected in the infant prior to the detection of the primary adrenal medullary tumor. Because of the rarity of the presentation, we also reviewed the related literature.
A 2-month-old male infant was admitted to the ocular oncology clinic with an amelanotic iris lesion in his right eye. He was the first child of a healthy, consanguineous (first cousins) couple born full term after an uncomplicated pregnancy. The parents noticed a gradually enlarging, whitish lesion in his right eye. It first appeared a few weeks after birth. On a routine visit to the general pediatrician at 2 months of age, the patient was referred to an ocular oncologist (Figure 1A). No yellowish skin lesions, characteristic for juvenile xanthogranuloma, were noted.
(A) Anterior segment photograph of a 2-month-old infant shows a whitish lesion in his right eye. (B) The preoperative anterior segment photograph demonstrates an amelanotic whitish iris lesion with hyphema in the anterior chamber. (C) The postoperative anterior segment photograph illustrates the well-preserved iris architecture after removal of the tumor.
The initial ophthalmologic examination under general anesthesia revealed hyphema in the anterior chamber and an amelanotic, whitish iris lesion in the right eye that measured 4 × 3 × 2 mm in basal dimensions (Figure 1B). This amelanotic, nodular hemorrhagic iris lesion without tumor seeding in the anterior chamber suggested a diagnosis of juvenile xanthogranuloma or a metastasis.
The patient underwent immediate surgical intervention, resulting in an uneventful complete excisional biopsy from the iris plane (Figure 1C). The pathologic examination was reported as stroma-poor, differentiated neuroblastoma (Figure 2A) with positive staining for neuron-specific enolase (NSE), synaptophysin (Figure 2B), and chromogranin. The patient was then referred to the pediatric oncology clinic. On admission, he was systemically well. His physical examination, complete blood count, blood chemistry, and peripheral smear were normal, except for increased serum NSE and spot urine vanillylmandelic acid levels. Abdominal ultrasonography and magnetic resonance imaging (MRI) revealed a heterogeneous left adrenal mass of approximately 40 × 44 mm encircling the renal artery. Biopsy of the left adrenal mass was also consistent with neuroblastoma (stroma-poor, differentiated) (Figure 2C–2D). A molecular examination was negative for MYCN gene amplification and a loss of 11q23, but it was positive for a gain of 17q25 and a loss of 1p36, with a DNA ploidy index of 0,37. No metastases were detected in the bone marrow aspiration and biopsy or on computer tomography (CT) scans of the thorax. MIBG scintigraphy was negative for any uptake including the adrenal mass.
(A) Iris tumor excisional biopsy shows a round cell malignant tumor infiltration similar to the adrenal tumor excision (hematoxylin–eosin stain, original magnification ×200). (B) Iris tumor excisional biopsy shows immunohistochemistry that synaptophysin is strongly and widely expressed in the entire tumor (hematoxylin–eosin stain, original magnification ×200). (C) Adrenal trucut biopsy shows a round cell malignant tumor with a minimal ganglionic differentiation (hematoxylin–eosin stain, original magnification ×200). (D) Adrenal tumor excisional biopsy shows a round cell malignant tumor in a fibrillary background (hematoxylin–eosin stain, original magnification ×400).
Because it was not clear whether the iris lesion was metastatic or independent primary, the patient was discussed at the local tumor board and accepted as stage IV. The Turkish Pediatric Oncology Group neuroblastoma treatment protocol (Regimen A7: vincristine, cyclophosphamide, and etoposide) was initiated.11 After four courses of chemotherapy, the residual adrenal mass was completely resected with negative surgical margins. Two additional courses of chemotherapy were administered after the resection. The patient completed a maintenance treatment of retinoic acid and is alive without disease after 36 months of follow-up.
There is a wide spectrum of iris tumors ranging from nevus to melanoma and juvenile xanthogranuloma to metastasis. According to the literature, iris tumors usually present in the fourth to fifth decade of life, and primary and metastatic iris tumors are uncommon in the pediatric age group. In a large clinical series of 3,680 cases with iris tumors collected over a 40-year period,12 12% of cases (449 cases) were children and adolescents younger than 20 years. Iris nevi was the most common diagnosis. In that series, other than 30 children with primary benign or malignant iris tumors, only three cases of metastatic iris lesions were reported without a single case of neuroblastoma (one rhabdomyosarcoma, one retinoblastoma, and one leukemia).
Between 2002 and 2016, a total of 1,942 neuroblastoma cases were registered to the Pediatric Cancer Registry in Turkey. The infant described here was the only neuroblastoma case with an iris lesion (0.07%) and also the only case of neuroblastoma in 192 cases treated in Istanbul University Oncology Institute between 1994 and 2017.13,14
The differential diagnosis of amelanotic iris lesions includes amelanotic nevus/melanoma, juvenile xanthogranuloma, metastasis, and rarely retinoblastoma.12,15 Hyphema may be the main presenting feature of a melanoma and nevus transformation into a melanoma. However, the clinical characteristics of our iris lesion and the young age of our patient led us to think of a differential diagnosis. An amelanotic, nodular, and hemorrhagic iris lesion without any tumor seeding in the anterior chamber was highly suggestive for a presumed diagnosis of juvenile xanthogranuloma or a metastasis rather than a retinoblastoma of anterior type. Despite the extreme rarity of anterior retinoblastoma, clinicians should bear in mind that a safer approach with a closed system, fine needle aspiration biopsy may be preferred to a surgical excision in such cases. In this case, excisional biopsy helped us define the atypical lesion as a neuroblastoma and led us to detect the primary adrenal medullary tumor, with subsequent management with chemotherapy and surgical resection.
Despite frequent and well-described metastases to the orbit and skull, neuroblastoma rarely originates from or metastasizes to the eye itself.7–10 Only three cases of neuroblastoma of the iris have been reported previously and are listed in Table 1. All of these cases were diagnosed during the neonatal period. Alio et al.8 reported a unilateral, single lesion with a mass effect and hyphema in the anterior chamber of the eye in a child with an adrenal mass. The case reported by Bowns et al.9 was unique because the iris lesions were bilateral and multiple in nature. Sekimoto et al.10 described a patient who had hypertension with increased levels of norepinephrine and renin. The pathologic examination of the excised primary lesion was totally necrotic with no clear evidence of neuroblastoma. None of the previous reports had a histopathological confirmation of the iris lesions because all of them were reported to have regressed with chemotherapy in parallel with the primary tumor. The current case is the only case in the literature with a histopathological confirmation of a metastatic neuroblastoma of the iris that was consistent with the histopathology of the adrenal lesion.
Cases With Neuroblastoma of the Iris
Staging was a challenge in our case because we were unable to determine whether the iris lesion represented a second primary or was just a metastatic lesion, given the lack of any other metastases. Bowns et al.9 were the first to propose the possibility of multiple primary neuroblastoma lesions arising simultaneously in utero. However, none of the reported cases, including the current one, had an isolated occurrence in the iris. All had an adrenal mass considered as the primary tumor without any other metastasis, with no place for speculation of the occurence of primary iris neuroblastoma. Our case report may emphasize that these tumors may be more common than previously thought because they are not searched for routinely as part of the work-up of neuroblastoma. Thus, a thorough ophthalmologic examination of neonates and infants with neuroblastoma can be performed at the initial diagnosis to further investigate the true incidence of small iris lesions in neuroblastoma that may have been unrecognized.
The origin of neuroblastoma in the eye is not clear. It has been postulated that the neuroblastoma may arise independently from the ciliary ganglion.7,8 It is possible that some neonates and infants with neuroblastoma have an iris lesion that may have been unrecognized and completely regressed after chemotherapy.
Iris lesions in neuroblastoma are extremely rare. We suggest that neonates and infants with neuroblastoma undergo an ophthalmologic examination at diagnosis to further investigate the true incidence of small iris lesions in neuroblastoma that may have been unrecognized. Neuroblastoma should be included in the differential diagnosis of amelanotic iris lesions of infants and young children.
- Matthay KK, Maris JM, Schleiermacher G, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078. doi:10.1038/nrdp.2016.78 [CrossRef]
- DuBois SG, Kalika Y, Lukens JN, et al. Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol. 1999;21:181–189. doi:10.1097/00043426-199905000-00005 [CrossRef]
- Smith SJ, Diehl NN, Smith BD, Mohney BG. Incidence, ocular manifestations, and survival in children with neuroblastoma: a population-based study. Am J Ophthalmol. 2010;149:677–682. doi:10.1016/j.ajo.2009.11.027 [CrossRef]
- Ahmed S, Goel S, Khandwala M, Agrawal A, Chang B, Simmons IG. Neuroblastoma with orbital metastasis: ophthalmic presentation and role of ophthalmologists. Eye (Lond). 2006;20:466–470. doi:10.1038/sj.eye.6701912 [CrossRef]
- Mahoney NR, Liu GT, Menacker SJ, Wilson MC, Hogarty MD, Maris JM. Pediatric Horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol. 2006;142:651–659. doi:10.1016/j.ajo.2006.05.047 [CrossRef]
- Rothenberg AB, Berdon WE, D'Angio GJ, Yamashiro DJ, Cowles RA. The association between neuroblastoma and opsoclonus-myoclonus syndrome: a historical review. Pediatr Radiol. 2009;39:723–726. doi:10.1007/s00247-009-1282-x [CrossRef]
- Inazawa N, Hatakeyama N, Hori T, et al. Primary orbital neuroblastoma in a 1-month-old boy. Pediatr Int. 2014;56:122–125. doi:10.1111/ped.12239 [CrossRef]
- Alio JL, Faci A, Garcia-Julian G, Martinez-Tello A. Anterior chamber metastasis from neuroblastoma. J Pediatr Ophthalmol Strabismus. 1982;19:299–301.
- Bowns GT, Walls RP, Murphree AL, Ortega J. Neonatal neuroblastoma metastatic to the iris. Cancer. 1983;52:929–931. doi:10.1002/1097-0142(19830901)52:5<929::AID-CNCR2820520531>3.0.CO;2-H [CrossRef]
- Sekimoto M, Hayasaka S, Setogawa T, Kishi K. Presumed iris metastasis from abdominal neuroblastoma. Ophthalmologica. 1991;203:8–11. doi:10.1159/000310218 [CrossRef]
- Aksoylar S, Varan A, Vergin C, et al. Treatment of high-risk neuroblastoma: national protocol results of the Turkish Pediatric Oncology Group. Cancer Res Ther. 2017;13:284–290. doi:10.4103/0973-1482.183205 [CrossRef]
- Shields CL, Kancherla S, Patel J, et al. Clinical survey of 3680 iris tumors based on patient age at presentation. Ophthalmology. 2012;119:407–414. doi:10.1016/j.ophtha.2011.07.059 [CrossRef]
- Kutluk MT, Yesilipek A. Turkish National Pediatric Cancer Registry 2002–2008 (Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society). J Clin Oncol. 2013;31 (suppl; abstr 10067).
- Kutluk MT, Yesilipek A. Pediatric cancer registry Turkey: 2009–2016 (TPOG & TPHD). J Clin Oncol. 2017; 35 (suppl; abstr e22015). doi:10.1200/JCO.2017.35.15_suppl.e22015 [CrossRef]
- Shields CL, Lally SE, Manjandavida FP, Leahey AM, Shields JA. Diffuse anterior retinoblastoma with globe salvage and visual preservation in 3 consecutive cases. Ophthalmology. 2016;123:378–384. doi:10.1016/j.ophtha.2015.09.040 [CrossRef]
Cases With Neuroblastoma of the Iris
|Study||Age||Sex||Stage||Primary Tumor Site||Histopathology||Iris Involvement||Histopathology||Treatment||Outcome||Iris Lesions|
|Alio et al.8||10 d||F||NA||Left adrenal||Resection||Right||–||CT, S||CR||Totally regressed|
|Bowns et al.9||3 d||F||IVS||Right adrenal||Biopsy (metastatic liver lesion)||Bilateral||–||CT||CR||Totally regressed|
|Sekimoto et al.10||2 mo||M||NA||Right adrenal||Resection (post-CT)||Left||–||CT, S||CR||Totally regressed|
|Current case||2 mo||M||IV||Left adrenal||Biopsy and resection (post-CT)||Right||Neuroblastoma, differentiated||CT, S||CR||CR since resection|