To determine the incidence, ophthalmic manifestations, and survival among children with neuroblastoma in a defined population.
Population-based retrospective cohort.
The medical records of all pediatric (<19 years) residents of Olmsted County, Minnesota, diagnosed with neuroblastoma from January 1, 1969, through December 31, 2008, were retrospectively reviewed.
Fourteen children were diagnosed with neuroblastoma as residents of Olmstead County, Minnesota, during the 40-year period, yielding an age- and gender-adjusted incidence of 11.8 (95% confidence interval [CI]: 5.6–18.0) per million patients <15 years of age. The calculated incidence for patients presenting before the age of 5 in this cohort was 1 in 5970 children (95% CI: 3920–12 580 children). The mean age at diagnosis for the 14 study patients was 22.5 months (range, 10.4–42.6 months). Six of the 14 (43%; 95% CI: 18%–71%) had ocular manifestations, including orbital metastasis in 6 (100%), proptosis and ecchymosis in 4 (67%), ptosis in 2 (33%), and strabismus in 1 (17%). The Kaplan-Meier rate of survival for all 14 children was 57% at 1 year (95% CI: 36%–90%) and 50% at 5 years (95% CI: 30%–84%), while the 6 with eye findings had a survival rate of 17% at 9 months (95% CI: 3%–100%).
The incidence of neuroblastoma in this population was 11.8 per million patients <15 years, with ophthalmic involvement observed in 6 of the 14 study patients (43%). Orbital metastasis in the 6 children in this cohort was associated with poor prognosis.
Neuroblastoma is the most common extracranial solid tumor among children under the age of 5 years, with a published incidence for that age of approximately 1 in 7000 children. Neuroblastic tumors are derived from primordial neural crest cells and ultimately populate the sympathetic ganglia, adrenal medulla, and other sites. Recent advancements in the understanding of tumor biology have aided in the diagnosis and medical management of this disease. However, cases of widespread metastasis, at times signaled by proptosis, ecchymosis, and other signs of orbital involvement, continue to have a poor prognosis. Ophthalmic manifestations are well documented and include proptosis, periorbital ecchymosis, Horner syndrome, opsoclonus/myoclonus, ocular motility defects, ptosis, and blindness.
Retrospective reviews conducted at large referral centers have found orbital metastasis in 10% to 20% of cases with neuroblastoma; however, there have been no population-based studies with which to compare these findings. The purposes of this study are to report the incidence and ophthalmic manifestations of neuroblastoma among a cohort of patients aged <19 years diagnosed as residents of Olmsted County, Minnesota, over a defined 40-year period, and to calculate survival rates based on ophthalmic involvement.
Subjects and Methods
The medical records of all pediatric (<19 years) patients residing in Olmsted County when diagnosed with neuroblastoma from January 1, 1969, through December 31, 2008, were retrospectively reviewed. Potential cases of neuroblastoma were identified using the resources of the Rochester Epidemiology Project, a medical record linkage system designed to capture data on any patient-physician encounter in Olmsted County, Minnesota. The racial distribution of Olmsted County residents in 1990 was 95.7% Caucasian, 3.0% Asian-American, 0.7% African-American, and 0.3% each Native American and other. The population of this county (106 470 in 1990) is relatively isolated from other urban areas, and essentially all medical care is provided to residents by the Mayo Clinic or the Olmsted Medical Group and their affiliated hospitals.
All diagnoses were entered into the Rochester Epidemiology Project database and residency status was verified by specially trained personnel. Children not living in Olmsted County at the time of their diagnosis were excluded. Neuroblastoma was defined in this study by clinical diagnosis, based on tumor biopsy results, catecholamine levels, and other systemic findings. Data collected included age at diagnosis, presenting symptoms, tumor staging, treatment received, ophthalmic involvement, and final outcome.
The cumulative probability of death was estimated using the Kaplan-Meier method. Continuous data were presented as a mean with the range. Categorical data were presented as counts and percentage. Annual age- and gender-specific incidence rates were constructed using the age- and gender-specific population figures for the county from the US Census. Estimates from the State of Minnesota were used to aid with linear interpolation of the 1970, 1980, 1990, and 2000 census years. The 95% confidence intervals were calculated with assumptions based on the Poisson distribution.
A total of 14 patients <19 years of age were diagnosed with neuroblastoma as residents of Olmsted County, Minnesota, during the 40-year study period, yielding an annual age- and gender-adjusted incidence of 11.8 cases per million children <15 years of age. All 14 cases presented before the age of 5, leading to an age-adjusted incidence of 33.5 cases per million, or 1 per 5970 children <5 years of age.
Clinical information, including age at diagnosis, presenting symptoms, ophthalmic site, tumor stage, and final outcome, was recorded for all 14 patients ( Table ). The mean age at diagnosis for all 14 was 22.5 months (range, 0.4–42.6 months) and 8 patients (57%) were female. The adrenal gland was the primary site in 10 of the 14 (72%); 3 (21%) were in the abdomen; and 1 (7%) was located in both the mediastinum and thoracic spine. Eight of the 14 (57%) were diagnosed as stage IV, with 2 (14%) each of stage II, III, and IVS.
|Case No. (Year at Diagnosis)||Age at Diagnosis (Months)||Gender||Presenting Symptoms||Primary Site||Ophthalmic Site/Manifestations||Ophthalmic Complications||Treatment||F/U Duration (Months)||Final Outcome||Stage|
|1 (1969)||42.6||F||Bilateral periorbital ecchymosis||R adrenal||Bilateral orbits/painful proptosis||Scleral hemorrhage||Chemotherapy||5.2||Pt deceased||IV|
|2 (1970)||21.5||M||Decreased appetite, listless, afebrile, hematuria||L adrenal||Right orbit/ptosis, right subconjunctival hemorrhage secondary to right temporal mass||Sluggish pupillary response||Radiation and chemotherapy||3.1||Pt deceased||IV|
|3 (1971)||16.5||F||Fever, rhinorrhea, cough, swollen L inguinal nodes||L adrenal||None||N/A||Resection, L adrenal and L inguinal nodes||309.6||Remission||IV|
|4 (1971)||4.6||F||Fever, vomiting, palpated RUQ mass||R adrenal||None||N/A||Resection, R adrenal mass and L supraclavicular mass||454.6||Remission||IVS|
|5 (1976)||29.7||F||Listless, purpura, thrombocytopenia, anemia||L adrenal||Bilateral orbits/right proptosis, with ecchymosis and ptosis. Bilateral temporal tumor nodules.||Difficulty depressing and abducting the right eye||Resection of L adrenal, L metastatic lymph nodes, L nephrectomy. Radiation and chemotherapy.||3.9||Pt deceased||IV|
|6 (1977)||34.8||F||Irritability, dehydration, fever, lethargy||L adrenal||Bilateral orbits/left proptosis with inward and medial displacement of the left globe. Bilateral metastasis.||Left esotropia with III, IV, and VI nerve palsies||Resection of L adrenal, L kidney, and L peri-aortic lymph nodes. Radiation and chemotherapy.||8.7||Pt deceased||IV|
|7 (1981)||24.5||M||Fatigue, fever, poor appetite, swollen L testicle||L adrenal||Left orbit/left proptosis and ecchymosis||N/A||Radiation and chemotherapy||3.5||Pt deceased||IV|
|8 (1987)||29.5||M||Bilateral periorbital ecchymosis, tender abdomen, ataxic gait||R abdomen||Bilateral orbits/bilateral periorbital ecchymosis. Left eye swelling with hemorrhage.||N/A||Resection of R abdominal mass and peri-aortic lymph nodes||9.1||Pt deceased||IV|
|9 (1988)||37.9||M||Hydronephrosis, noted abdominal mass||R abdomen||None||N/A||Resection of abdominal mass. Chemotherapy.||245.4||Remission||III|
|10 (1990)||36.2||F||Decreased appetite, irritability, palpable LUQ mass||Abdomen||None||N/A||Chemotherapy||17.5||Pt deceased||IV|
|11 (1993)||31.3||F||Ataxia, irritability, fever, urinary incontinence||R adrenal||None||N/A||Resection of R adrenal tumor. Chemotherapy.||142.1||Remission||III|
|12 (1997)||4.9||M||6-week history of cough, nasal congestion; chest radiograph showed mass||Mediastinum, thoracic spine||None||N/A||Resection of epidural tumor and mediastinal mass||144.0||Remission||II|
|13 (1997)||0.6||M||Irritability, vomiting, diarrhea||L adrenal||None||N/A||Resection of L adrenal tumor||142.9||Remission||II|
|14 (2004)||0.4||F||Prenatal ultrasound||R adrenal||None||N/A||Resection of R adrenal tumor. Chemotherapy.||60.6||Remission||IVS|
Ophthalmic involvement was noted in 6 of the 14 cases (43%; 95% CI: 18%–71%) and was the presenting symptom in 2 (14%). Metastasis to the orbit was seen in all 6 cases with ocular involvement. There were 4 bilateral presentations and 1 each affecting the left and right orbit respectively. Proptosis and ecchymosis occurred in 4 of the 6 cases (67%), ptosis was observed in 2 (33%), and 1 patient (17%) had strabismus. The 9-month survival in patients with orbital metastasis was 17% (95% CI: 3%–100%) with an average age at diagnosis of 30.3 months (range, 21.5–42.6 months).
Seven of the 14 cases achieved clinical remission, yielding a survival rate of 50% (95% CI: 30%–84%) at 18 months ( Figure 1 ). Survival was heavily age- and stage-dependent, and overall survival varied with the decade of the study, with markedly improved survival noted in cases presenting after 1980 ( Figure 2 ). The 4 cases that presented before 1 year of age had a 100% 5-year survival, while the 10 cases presenting after their first birthday had a 5-year survival of only 30%. The 5-year survival for all 8 stage IV presentations was 13%. The mean survival for all 14 cases was 110.7 months (range, 3.1–454.6 months), while average survival for those with ocular involvement was only 5.6 months (range, 3.1–9.1 months).