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Ocular Involvement in Neuroblastoma: Prognostic Implications
Ocular Involvement in Neuroblastoma: Prognostic Implications MARIA A. MUSARELLA, MD,* HELENS. L. CHAN, MD,t GERRIT DeBOER, PhD,* BRENDA L. GALLIE, MD, FRCS(C)*
Abstract: Neuroblastoma is one of the commonest childhood malignancies. The most important prognostic factor is age at diagnosis; early diagnosis, when the tumor is still localized and surgically resectable, is second in importance. On retrospective review of children seen at the Hospital for Sick Children, ophthalmic involvement was seen in 80 of 405 (20%). The three major eye signs of neuroblastoma, proptosis, Horner's syndrome and opsoclonus, are closely related to the site, stage of tumor, and outcome of the patient. Proptosis or periorbital ecchymosis due to orbital metastases was present in 60 of 80 children (bilaterally in 33). The 3-year survival rate was 11.2%. In 53 of 60 cases with orbital metastases the neuroblastoma originated in the abdomen. Unilateral Horner's syndrome occurred in 14 children, as the presenting sign in 9, related to localized disease in 11 and in a favorable location (cervical or thoracic neuroblastoma) in 8. The 3-year survival rate was 78.6%. Opsoclonusmyoclonus was the presenting sign of occult, localized neuroblastoma in all 9 children in whom it occurred. The 3-year survival rate was 100%. For all presentations, girls had a significantly better survival rate than boys (48.7% vs. 22.4%). Children presenting with any of these ophthalmological signs should undergo thorough and repeated investigations searching for neuroblastoma. · [Key words: Horner's syndrome, neuroblastoma, opsoclonus, prognosis, proptosis.] Ophthalmology 91:936-940, 1984
Neuroblastoma, one of the commonest childhood malignancies, arises from embryonic neuroblastic tissue in the abdomen (60%), thoracic, cervical or pelvic regions. Presentation of neuroblastoma depends on the site of origin. Prognosis is influenced primarily by the patient's age, and by the stage and site of the tumor. Survival is
From the Departments of Pediatric Ophthalmology* and Pediatric Hematology and Oncology,t The Hospital for Sick Children, and the Ontario Cancer lnstitute,:j: Toronto, Canada. Presented at the ARVO Spring meeting in Sarasota, Florida, May 1983. Supported in part by a National Children Eye Care Foundation Fellowship. Dr. Musarella is the recipient of the Heed-Richard G. Scobee Fellowship. Reprint requests to Brenda L. Gallie, MD, FRCS(C), The Ontario Cancer Institute, 500 Shebourne Street, Toronto, Ontario M4X 1K9.
936
highest in children younger than 2 years of age, and in those with intrathoracic tumor, and stage I, II and IV-S disease (disseminated neuroblastoma with marrow, liver, or skin involvement, but with no radiologic evidence of bony metastases. 1•2 The classical features of metastatic neuroblastoma to the orbits are well known. 3- 6 Less familiar to the ophthalmologist are the other ocular findings of neuroblastoma and their contribution towards the early diagnosis and prognosis of this highly malignant tumor. We retrospectively reviewed the charts of 405 children with neuroblastoma specifically to study the ocular findings of metastatic and non-metastatic neuroblastoma. We found that the three major eye signs of neuroblastoma: proptosis, Horner's syndrome and opsoclonus, are closely related to the site and the stage of the tumor, and to the outcome of the patient.
MUSARELLA, et al
0 Fig 1. A 4 year old boy with left Horner's syndrome (relative pupil sizes are indicated by circles) and proptosis from disseminated neuroblastoma originating from left paraspinal region. Note area of ecchymosis on right upper eyelid (arrow).
METHODS The records of all children with neuroblastoma at the Hospital for Sick Children in Toronto since 1919 were reviewed. Four hundred five cases of verified neuroblasto~a were found. In each case the clinical history was available for examination. The charts were reviewed for any documented ocular manifestations at diagnosis and throughout the course of the disease. Patients with eye signs of increased intracranial pressure were excluded because this ocular finding is not specific for neuroblastoma, and _can occur with any primary or secondary intracranial mahgnancy. The primary site was recorded when known. Appropriate follow-up was present in all cases included in this study. Detailed ocular examinations were performed on some but not all children (either because they were terminally ill or because ophthalmic consultation had not been requested). The diagnosis of Homer's syn-
Fig 2. A 4-month-old infant born with right ptosis and right miosis; found to have a right thoracic neuroblastoma.
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NEUROBLASTOMA
drome was made based on the presence of ptosis and/or miosis, with or without heterochromia. Pharmacological testing with cocaine and paredrine was not performed. The survival time was recorded on each patient and was reported as the time from presentation to death or last follow-up visit. The cases were subdivided into the three major eye signs of neuroblastoma. Actuarial survival curves were constructed for each group and for both sexes according to the Kaplan-Meier method. 7 A WilcoxonGehan test8 was performed to determine the statistical significance between the groups and sexes.
RESULTS Ophthalmological involvement occurred in 80 ( 19.8%) of the 405 neuroblastoma patients. The ocular symptoms were the presenting signs of neuroblastoma in 33 (8.1%) children. The most frequent ocular sign of neuroblastoma was metastases to the soft tissue of the orbit, present in 60 of the 80 children. Orbital metastases presented commonly as unilateral or bilateral proptosis (42 cases; Fig 1). Periorbital ecchymosis was present concomitantly with proptosis in 22 patients. Other signs of orbital metastases were periorbital swelling, ptosis and swelling of the adjacent frontal and zygomatic bones. In 33 children, orbital metastases occurred bilaterally. Proptosis was the presenting sign of neuroblastoma in 15 patients. In 53 of the 60 cases with orbital metastases, the neuroblastoma originated in the abdomen (39 adrenal, 14 paraspinal). Only one child with unilateral nonecchymotic proptosis had cervical neuroblastoma. The mediastinum or thorax was the site of origin in an additional four children with orbital metastases. The remaining two children had disseminated disease at the time of presentation. The mean age of presentation of neuroblastoma in this group of 60 patients was 26.3 months (2.2 years). Fiftyfive of 60 children with orbital metastases died from 1 week to 3.5 years after diagnosis (6 months median survival). The remaining 5 children are in remission at 1, 1, 10, 11, and 17 years, respectively, after diagnosis of neuroblastoma. The 3-year survival rate was 11.2%. Of the 15 children whose initial presentation was proptosis, 14 died within 12 months (mean, 7 months), while 1 patient was a long-term survivor 11 years post-diagnosis. Unilateral Homer's syndrome (14 cases) was the next most frequent ocular sign of neuroblastoma. Homer's syndrome was present prior to thoracic or cervical surgical ~ntervention for tumor excision. These children had ptosis, m some cases intermittently, miosis and/or heterochromia iridis (3 cases; Figs 2, 3). As suggested by Giles and Henderson, any clinical interruption of the sympathetics to the eye has been considered evidence of Homer's syndrome.9 Homer's syndrome was ipsilateral to a cervical or thoracic neuroblastoma in 13 children, while one child had an unexplained left Homer's syndrome with a left adrenal neuroblastoma. Eleven of these 14 cases had localized disease. Two infants had congenital Homer's syndrome with congenital cervical neuroblastoma. Homer's syndrome was the presenting sign in 9 children. The mean 937
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Fig 3. Girl with left Horner's syndrome due to localized left cervical neuroblastoma. Left. left pupil smaller than right. Circles indicate relative pupil sizes. Right, left cervical mass indicated by double arrows.
age of the 14 children was 2.5 years. Eleven of the children developed their neuroblastoma prior to 18 months of age. The 3-year survival rate in this group of patients was 78.6%. Eleven of the 14 children are alive from 2 to 20 years post diagnosis (mean, 8 years). The remaining 3 children with Horner's syndrome died of disease at 3, 4, and 5 months. Two children with Horner's syndrome also had opsoclonus-myoclonus, and both are alive 2 and 10 years post diagnosis. Nine children has opsoclonus-myoclonus associated with neuroblastoma and all had localized disease ( 5 thoracic and/or cervical, 3 adrenal, and 1 pelvic). All presented with "dancing eyes", consisting of rapid multidirectional eye movements, myoclonus and truncal ataxia. The mean age of all 9 children was 18 months. All nine children with opsoclonus-myoclonus are alive and free of recurrent tumor with a mean follow-up period of 3. 7 years (Table 1) (Figure 4). Girls had a much better 3-year survival rate (47.8%) than boys (22.4% ). This difference was statistically significant (P = 0.037) (Fig 5).
DISCUSSION Neuroblastoma occurs most frequently in the young pediatric age group (median age, 2 years). 10 Seventy-two percent of tumors arise in abdomen and 13% arise in the mediastinum. The remainder arise in paraspinal and pelvic regions, but in some metastatic neuroblastoma the site of the primary is unknown. 11 Seventy-five percent of 938
patients excrete increased amounts of catecholamine metabolites in the urine. The prognosis in neuroblastoma is influenced mainly by age, stage and primary tumor site. The 2-year relapse-free survival rate is 75% in children diagnosed before 1 year of age, and 12% after 2 years of age. 10 Thoracic tumors are more favorable than abdominal lesions. The survival rate in neuroblastoma, despite treatment, has improved little in the past two decades. Approximately 70% of the patients have widespread disease at the time of diagnosis and their responses to radiation and chemotherapeutic agents are variable and transient. Early diagnosis, when the tumor is still localized and surgically resectable is an important factor influencing the prognosis. Since ophthalmological involvement is seen in approxTable 1. Review of 405 Neuroblastoma Patients Ophthalmic Manifestation
No. of Patients*
Primary Site (no.)
Orbital Horner's Syndrome Opsoclonus
60 14
Abdomen (53) Cervical, thoracic (12) Mediastinal (3) Adrenal (3) Paraspinal (2) Pelvic (1)
9
3-Year Survival Rate 11.2% 78.6% 100%
* 1 child with proptosis had Horner's syndrome and 2 children with opsoclonus had Horner's syndrome.
MUSARELLA, et al
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Fig 4. Actuarial survival curve for the three major eye signs of neuroblastoma: orbital (solid line) vs. Horner's syndrome (dashed line) (P < 0.0005); orbital (solid line) vs. opsoclonus (dash-dot line) (P < 0.005).
imately 20% of patients with neuroblastoma and in 8.1% is the presenting feature, the ophthalmologist may play a major role in the early diagnosis of this disease. Two of the ocular signs, Homer's syndrome 12·13 and opsoclonus, 14·15 are frequently associated with localized neuroblastoma, while orbital involvement is almost exclusively associated with disseminated tumor. 2·3·5 The presence of orbital metastases, though well recognized in neuroblastoma, has not been previously looked at in relation to prognosis, and the frequency has not been accurately established in a large series of children with neuroblastoma. The 3-year survival rate for neuroblastoma has been estimated to be 23%. 16 Our data shows a poorer
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Fig 5. Actuarial survival curve of girls (solid line) vs. boys (dashed line): 48.7% 3-year survival rate for girls vs. 22.4% for boys (P = 0.037).
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prognosis in patients who developed orbital metastases (3-year survival rate, 11.2% ). The differences in survival rate between the orbital metastases and the Homer's syndrome groups, and the orbital metastases and the opsoclonus groups were statistically highly significant (P < 0.0005 in both cases). The poor prognosis in our patients with orbital metastases is related to the predominance with children with advanced disease involving the bony orbit, with an unfavorable age (mean age, 2.2 years) and an unfavorable primary tumor site (88% in the abdomen). In contrast, neuroblastoma associated with Homer's syndrome has an excellent survival rate of 78.6% in our series. Like others, 12•13·17 we find a predominance of patients with localized disease (11 of 14 cases) at a favorable location (13 of 14 cases has cervical or thoracic neuroblastoma), although these children were in an unfavorable age group (mean, 2.5 years). The nine children with opsoclonus-myoclonus in our series had the best survival rate ( 100% ), despite unfavorable location (abdomen) in four children. It has been proposed that an auto-immune factor, possibly an antibody directed against a neuroblastoma antigen, cross reacts with a common antigen in the cerebellar cells, resulting in cerebellar damage and thus opsoclonus-myoclonus. 18 The excellent prognosis of patients with this rare syndrome may be explained partially by earlier diagnosis and a higher percentage of Stage I, II and IV-S. However, these factors do not explain the long-term survival in children with Stage III and Stage IV disease. It is hypothesized that the opsoclonus-myoclonus in these patients may be pathogenetically related to an autoimmune factor which controls growth and spread of the neuroblastoma. In our series, the natural history of opsomyoclonus could be studied since the children had been followed for periods ranging from 18 to 123 months (mean, 46 months). Other than the one child where the opsoclonus had disappeared before diagnosis, most children (5 cases) had slowly resolving opsomyoclonus over the next 1 to 2 years. In a third of the children the affliction persisted, and was associated with mental retardation in one of the nine patients. A higher frequency of cerebellar deficit (64%) and mental retardation (34%) was noted by Senelike et al 19 in 22 cases collected from the literature. Relatively few authors have reported survival rates separately for the two sexes. Survival rate for both sexes have been compared in four pevious papers; 16·21 -23 in three of the four, the authors found that the prognosis was better in girls; the fourth paper found that the prognosis was better in boys. In only one paper was the difference statistically significant. 16 In our series, the girls had better survival rate than boys and the difference was statistically significant. The better prognosis in girls has been considered to be due to a greater likelihood of tumor maturation.23 Although orbital metastases occur frequently choroidal metastasis appear to be rare. Unfortunately, because of the retrospective nature of this study, a definitive statement about choroidal metastases from neuroblastoma can not be made. Rothman and Blankstein had reported
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extensive infiltration of choroidal vessels with neuroblastoma at autopsy in a 2.5-year-old child who had minimal clinical evidence of involvement of the choroid. Other studies have also not encountered intraocular metastasis to the choroid. 5 Recently, hypopyon was reported in a child with disseminated neuroblastoma; however, an anterior chamber tap was not done to confirm the nature of the cells. 25 In conclusion, we observed three common eye signs associated with neuroblastoma. We recommend that children presenting with any of these features undergo thorough and repeated investigations (chest and abdominal radiographs, computed tomograms and urinary catecholamines) to look for an occult neuroblastoma. Prospective study of children with proptosis, Horner's syndrome or opsomyoclonus will reveal the proportion of children who present with these ocular signs that have neuroblastoma.
REFERENCES 1. Evans AE, D'Angio GJ, Randolph J. A proposed staging for children with neuroblastoma; children's cancer study group A. Cancer 1971; 27:374-8. 2. D'Angio GJ, Evans AE, Koop CE. Special pattern of wide· spread neuroblastoma with a favourable prognosis. Lancet 1971; 1:1046-9. 3. Alfano JE. Ophthalmological aspects of neuroblastomatosis: a study of 53 verified cases. Trans Arn Acad Ophthalmol Otolaryngol1968; 72:830-48. 4. Mortada A. Clinical characteristics of early orbital metastatic neuroblastoma. Am J Ophthalmol1967; 63:1787-93. 5. Albert DM, Rubenstein RA, Scheie HG. Tumor metastasis to the eye. II. Clinical study in infants and children. Am J Ophthalmol 1967; 63:727-32. 6. Apple DJ. Metastatic orbital neuroblastoma originating in the cervical sympathetic ganglionic chain. Am J Ophthalmol 1969; 68:1093-5. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 8. Gehan EA. A generalized Wilcoxon test for comparing arbitrarily singlycensored samples. Biometrika 1965; 52:203-23.
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9. Giles CL, Henderson JW. Horner's Syndrome: an analysis of 216 cases. Am J Ophthalmol1958; 46:289-96. 10. Maurer HM. Current concepts in cancer. Solid tumors in children. N Engl J Med 1978; 299:1345-8. 11. The Staff of the Royal Children's Hospital Melbourne. Tumours of the Adrenal Medulla. In: Jones PG, Campbell PE, eds. Tumours of Infancy and Childhood. London: Blackwell Scientific, 1976; Chapter 18. 12. Beckerman BL, Seaver R. Congenital Horner's syndrome and thoracic neuroblastoma. J Pediatr Ophthalmol Strabismus 1978; 15:24-5. 13. Jaffe N, Cassady R, Petersen R, Traggis D. Heterochromia and Horner syndrome associated with cervical and mediastinal neuroblastoma. J Pediatr 1975; 87:75-7. 14. Solomon GE, Chutorian AM. Opsoclonus and occult neuroblastoma. N Engl J Med 1968; 279:475-7. 15. Sandok BA, Kranz H. Opsoclonus as the initial manifestation of occult neuroblastoma. Arch Ophthalmol 1971; 86:235-6. 16. Wilson LMK, Draper GJ. Neuroblastoma, its natural history and prognosis: A study of 487 cases. Br Med J 1974; 3:301-7. 17. Filler RM, Traggis DG, Jaffe N, Vawter GF. Favorable outlook for children with mediastinal neuroblastoma. J Pediatr Surg 1972; 7:13643. 18. Altman AJ, Baehner RL. Favorable prognosis for survival in children with coincident opso-myoclonus and neuroblastoma. Cancer 1976; 37:846-52. 19. Senelick RC, Bray PF, Lahey ME, et al. Neuroblastoma and myoclonic encephalopathy: two cases and a review of the literature. J Pediatr Surg 1973; 8:623-32. 20. deLorimier AA, Bragg KU, Linden G. Neuroblastoma in childhood. Am J Dis Child 1969; 118:441-50. 21. McFarland J, Sappington SW. A ganglioneuroma in the neck of a child. Am J Pathol 1935; 11 :429-48. 22. Stella JG, Schweisguth 0, Schlienger M. Neuroblastoma; a study of 144 cases treated in the lnstitut Gustav-Roussy over a period of 7 years. Am J Roentgenol Radium Ther Nucl Med 1970; 108:325-32. 23. Willis RA. The Pathology of the Tumours of Children. Edinburgh and London: Oliver and Boyd, 1962; 4. 24. Bothman L, Blankstein SS. The eye in adrenal sympathicoblastoma (neuroblastoma); importance of ocular findings, with first pathologic report of metastasic tumor in choroid. Arch Ophthalmol 1942; 27:746-61. 25. Alia JL, FaciA, Garcia-Julian G, Martinez-Tello A. Anterior chamber metastasis from neuroblastoma. J Pediatr Ophthalmol Strabismus 1982; 19:299-301.
Abstract: Neuroblastoma is one of the commonest childhood malignancies. The most important prognostic factor is age at diagnosis; early diagnosis, when the tumor is still localized and surgically resectable, is second in importance. On retrospective review of children seen at the Hospital for Sick Children, ophthalmic involvement was seen in 80 of 405 (20%). The three major eye signs of neuroblastoma, proptosis, Horner's syndrome and opsoclonus, are closely related to the site, stage of tumor, and outcome of the patient. Proptosis or periorbital ecchymosis due to orbital metastases was present in 60 of 80 children (bilaterally in 33). The 3-year survival rate was 11.2%. In 53 of 60 cases with orbital metastases the neuroblastoma originated in the abdomen. Unilateral Horner's syndrome occurred in 14 children, as the presenting sign in 9, related to localized disease in 11 and in a favorable location (cervical or thoracic neuroblastoma) in 8. The 3-year survival rate was 78.6%. Opsoclonusmyoclonus was the presenting sign of occult, localized neuroblastoma in all 9 children in whom it occurred. The 3-year survival rate was 100%. For all presentations, girls had a significantly better survival rate than boys (48.7% vs. 22.4%). Children presenting with any of these ophthalmological signs should undergo thorough and repeated investigations searching for neuroblastoma. · [Key words: Horner's syndrome, neuroblastoma, opsoclonus, prognosis, proptosis.] Ophthalmology 91:936-940, 1984
Neuroblastoma, one of the commonest childhood malignancies, arises from embryonic neuroblastic tissue in the abdomen (60%), thoracic, cervical or pelvic regions. Presentation of neuroblastoma depends on the site of origin. Prognosis is influenced primarily by the patient's age, and by the stage and site of the tumor. Survival is
From the Departments of Pediatric Ophthalmology* and Pediatric Hematology and Oncology,t The Hospital for Sick Children, and the Ontario Cancer lnstitute,:j: Toronto, Canada. Presented at the ARVO Spring meeting in Sarasota, Florida, May 1983. Supported in part by a National Children Eye Care Foundation Fellowship. Dr. Musarella is the recipient of the Heed-Richard G. Scobee Fellowship. Reprint requests to Brenda L. Gallie, MD, FRCS(C), The Ontario Cancer Institute, 500 Shebourne Street, Toronto, Ontario M4X 1K9.
936
highest in children younger than 2 years of age, and in those with intrathoracic tumor, and stage I, II and IV-S disease (disseminated neuroblastoma with marrow, liver, or skin involvement, but with no radiologic evidence of bony metastases. 1•2 The classical features of metastatic neuroblastoma to the orbits are well known. 3- 6 Less familiar to the ophthalmologist are the other ocular findings of neuroblastoma and their contribution towards the early diagnosis and prognosis of this highly malignant tumor. We retrospectively reviewed the charts of 405 children with neuroblastoma specifically to study the ocular findings of metastatic and non-metastatic neuroblastoma. We found that the three major eye signs of neuroblastoma: proptosis, Horner's syndrome and opsoclonus, are closely related to the site and the stage of the tumor, and to the outcome of the patient.
MUSARELLA, et al
0 Fig 1. A 4 year old boy with left Horner's syndrome (relative pupil sizes are indicated by circles) and proptosis from disseminated neuroblastoma originating from left paraspinal region. Note area of ecchymosis on right upper eyelid (arrow).
METHODS The records of all children with neuroblastoma at the Hospital for Sick Children in Toronto since 1919 were reviewed. Four hundred five cases of verified neuroblasto~a were found. In each case the clinical history was available for examination. The charts were reviewed for any documented ocular manifestations at diagnosis and throughout the course of the disease. Patients with eye signs of increased intracranial pressure were excluded because this ocular finding is not specific for neuroblastoma, and _can occur with any primary or secondary intracranial mahgnancy. The primary site was recorded when known. Appropriate follow-up was present in all cases included in this study. Detailed ocular examinations were performed on some but not all children (either because they were terminally ill or because ophthalmic consultation had not been requested). The diagnosis of Homer's syn-
Fig 2. A 4-month-old infant born with right ptosis and right miosis; found to have a right thoracic neuroblastoma.
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drome was made based on the presence of ptosis and/or miosis, with or without heterochromia. Pharmacological testing with cocaine and paredrine was not performed. The survival time was recorded on each patient and was reported as the time from presentation to death or last follow-up visit. The cases were subdivided into the three major eye signs of neuroblastoma. Actuarial survival curves were constructed for each group and for both sexes according to the Kaplan-Meier method. 7 A WilcoxonGehan test8 was performed to determine the statistical significance between the groups and sexes.
RESULTS Ophthalmological involvement occurred in 80 ( 19.8%) of the 405 neuroblastoma patients. The ocular symptoms were the presenting signs of neuroblastoma in 33 (8.1%) children. The most frequent ocular sign of neuroblastoma was metastases to the soft tissue of the orbit, present in 60 of the 80 children. Orbital metastases presented commonly as unilateral or bilateral proptosis (42 cases; Fig 1). Periorbital ecchymosis was present concomitantly with proptosis in 22 patients. Other signs of orbital metastases were periorbital swelling, ptosis and swelling of the adjacent frontal and zygomatic bones. In 33 children, orbital metastases occurred bilaterally. Proptosis was the presenting sign of neuroblastoma in 15 patients. In 53 of the 60 cases with orbital metastases, the neuroblastoma originated in the abdomen (39 adrenal, 14 paraspinal). Only one child with unilateral nonecchymotic proptosis had cervical neuroblastoma. The mediastinum or thorax was the site of origin in an additional four children with orbital metastases. The remaining two children had disseminated disease at the time of presentation. The mean age of presentation of neuroblastoma in this group of 60 patients was 26.3 months (2.2 years). Fiftyfive of 60 children with orbital metastases died from 1 week to 3.5 years after diagnosis (6 months median survival). The remaining 5 children are in remission at 1, 1, 10, 11, and 17 years, respectively, after diagnosis of neuroblastoma. The 3-year survival rate was 11.2%. Of the 15 children whose initial presentation was proptosis, 14 died within 12 months (mean, 7 months), while 1 patient was a long-term survivor 11 years post-diagnosis. Unilateral Homer's syndrome (14 cases) was the next most frequent ocular sign of neuroblastoma. Homer's syndrome was present prior to thoracic or cervical surgical ~ntervention for tumor excision. These children had ptosis, m some cases intermittently, miosis and/or heterochromia iridis (3 cases; Figs 2, 3). As suggested by Giles and Henderson, any clinical interruption of the sympathetics to the eye has been considered evidence of Homer's syndrome.9 Homer's syndrome was ipsilateral to a cervical or thoracic neuroblastoma in 13 children, while one child had an unexplained left Homer's syndrome with a left adrenal neuroblastoma. Eleven of these 14 cases had localized disease. Two infants had congenital Homer's syndrome with congenital cervical neuroblastoma. Homer's syndrome was the presenting sign in 9 children. The mean 937
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Fig 3. Girl with left Horner's syndrome due to localized left cervical neuroblastoma. Left. left pupil smaller than right. Circles indicate relative pupil sizes. Right, left cervical mass indicated by double arrows.
age of the 14 children was 2.5 years. Eleven of the children developed their neuroblastoma prior to 18 months of age. The 3-year survival rate in this group of patients was 78.6%. Eleven of the 14 children are alive from 2 to 20 years post diagnosis (mean, 8 years). The remaining 3 children with Horner's syndrome died of disease at 3, 4, and 5 months. Two children with Horner's syndrome also had opsoclonus-myoclonus, and both are alive 2 and 10 years post diagnosis. Nine children has opsoclonus-myoclonus associated with neuroblastoma and all had localized disease ( 5 thoracic and/or cervical, 3 adrenal, and 1 pelvic). All presented with "dancing eyes", consisting of rapid multidirectional eye movements, myoclonus and truncal ataxia. The mean age of all 9 children was 18 months. All nine children with opsoclonus-myoclonus are alive and free of recurrent tumor with a mean follow-up period of 3. 7 years (Table 1) (Figure 4). Girls had a much better 3-year survival rate (47.8%) than boys (22.4% ). This difference was statistically significant (P = 0.037) (Fig 5).
DISCUSSION Neuroblastoma occurs most frequently in the young pediatric age group (median age, 2 years). 10 Seventy-two percent of tumors arise in abdomen and 13% arise in the mediastinum. The remainder arise in paraspinal and pelvic regions, but in some metastatic neuroblastoma the site of the primary is unknown. 11 Seventy-five percent of 938
patients excrete increased amounts of catecholamine metabolites in the urine. The prognosis in neuroblastoma is influenced mainly by age, stage and primary tumor site. The 2-year relapse-free survival rate is 75% in children diagnosed before 1 year of age, and 12% after 2 years of age. 10 Thoracic tumors are more favorable than abdominal lesions. The survival rate in neuroblastoma, despite treatment, has improved little in the past two decades. Approximately 70% of the patients have widespread disease at the time of diagnosis and their responses to radiation and chemotherapeutic agents are variable and transient. Early diagnosis, when the tumor is still localized and surgically resectable is an important factor influencing the prognosis. Since ophthalmological involvement is seen in approxTable 1. Review of 405 Neuroblastoma Patients Ophthalmic Manifestation
No. of Patients*
Primary Site (no.)
Orbital Horner's Syndrome Opsoclonus
60 14
Abdomen (53) Cervical, thoracic (12) Mediastinal (3) Adrenal (3) Paraspinal (2) Pelvic (1)
9
3-Year Survival Rate 11.2% 78.6% 100%
* 1 child with proptosis had Horner's syndrome and 2 children with opsoclonus had Horner's syndrome.
MUSARELLA, et al
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Fig 4. Actuarial survival curve for the three major eye signs of neuroblastoma: orbital (solid line) vs. Horner's syndrome (dashed line) (P < 0.0005); orbital (solid line) vs. opsoclonus (dash-dot line) (P < 0.005).
imately 20% of patients with neuroblastoma and in 8.1% is the presenting feature, the ophthalmologist may play a major role in the early diagnosis of this disease. Two of the ocular signs, Homer's syndrome 12·13 and opsoclonus, 14·15 are frequently associated with localized neuroblastoma, while orbital involvement is almost exclusively associated with disseminated tumor. 2·3·5 The presence of orbital metastases, though well recognized in neuroblastoma, has not been previously looked at in relation to prognosis, and the frequency has not been accurately established in a large series of children with neuroblastoma. The 3-year survival rate for neuroblastoma has been estimated to be 23%. 16 Our data shows a poorer
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Fig 5. Actuarial survival curve of girls (solid line) vs. boys (dashed line): 48.7% 3-year survival rate for girls vs. 22.4% for boys (P = 0.037).
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prognosis in patients who developed orbital metastases (3-year survival rate, 11.2% ). The differences in survival rate between the orbital metastases and the Homer's syndrome groups, and the orbital metastases and the opsoclonus groups were statistically highly significant (P < 0.0005 in both cases). The poor prognosis in our patients with orbital metastases is related to the predominance with children with advanced disease involving the bony orbit, with an unfavorable age (mean age, 2.2 years) and an unfavorable primary tumor site (88% in the abdomen). In contrast, neuroblastoma associated with Homer's syndrome has an excellent survival rate of 78.6% in our series. Like others, 12•13·17 we find a predominance of patients with localized disease (11 of 14 cases) at a favorable location (13 of 14 cases has cervical or thoracic neuroblastoma), although these children were in an unfavorable age group (mean, 2.5 years). The nine children with opsoclonus-myoclonus in our series had the best survival rate ( 100% ), despite unfavorable location (abdomen) in four children. It has been proposed that an auto-immune factor, possibly an antibody directed against a neuroblastoma antigen, cross reacts with a common antigen in the cerebellar cells, resulting in cerebellar damage and thus opsoclonus-myoclonus. 18 The excellent prognosis of patients with this rare syndrome may be explained partially by earlier diagnosis and a higher percentage of Stage I, II and IV-S. However, these factors do not explain the long-term survival in children with Stage III and Stage IV disease. It is hypothesized that the opsoclonus-myoclonus in these patients may be pathogenetically related to an autoimmune factor which controls growth and spread of the neuroblastoma. In our series, the natural history of opsomyoclonus could be studied since the children had been followed for periods ranging from 18 to 123 months (mean, 46 months). Other than the one child where the opsoclonus had disappeared before diagnosis, most children (5 cases) had slowly resolving opsomyoclonus over the next 1 to 2 years. In a third of the children the affliction persisted, and was associated with mental retardation in one of the nine patients. A higher frequency of cerebellar deficit (64%) and mental retardation (34%) was noted by Senelike et al 19 in 22 cases collected from the literature. Relatively few authors have reported survival rates separately for the two sexes. Survival rate for both sexes have been compared in four pevious papers; 16·21 -23 in three of the four, the authors found that the prognosis was better in girls; the fourth paper found that the prognosis was better in boys. In only one paper was the difference statistically significant. 16 In our series, the girls had better survival rate than boys and the difference was statistically significant. The better prognosis in girls has been considered to be due to a greater likelihood of tumor maturation.23 Although orbital metastases occur frequently choroidal metastasis appear to be rare. Unfortunately, because of the retrospective nature of this study, a definitive statement about choroidal metastases from neuroblastoma can not be made. Rothman and Blankstein had reported
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extensive infiltration of choroidal vessels with neuroblastoma at autopsy in a 2.5-year-old child who had minimal clinical evidence of involvement of the choroid. Other studies have also not encountered intraocular metastasis to the choroid. 5 Recently, hypopyon was reported in a child with disseminated neuroblastoma; however, an anterior chamber tap was not done to confirm the nature of the cells. 25 In conclusion, we observed three common eye signs associated with neuroblastoma. We recommend that children presenting with any of these features undergo thorough and repeated investigations (chest and abdominal radiographs, computed tomograms and urinary catecholamines) to look for an occult neuroblastoma. Prospective study of children with proptosis, Horner's syndrome or opsomyoclonus will reveal the proportion of children who present with these ocular signs that have neuroblastoma.
REFERENCES 1. Evans AE, D'Angio GJ, Randolph J. A proposed staging for children with neuroblastoma; children's cancer study group A. Cancer 1971; 27:374-8. 2. D'Angio GJ, Evans AE, Koop CE. Special pattern of wide· spread neuroblastoma with a favourable prognosis. Lancet 1971; 1:1046-9. 3. Alfano JE. Ophthalmological aspects of neuroblastomatosis: a study of 53 verified cases. Trans Arn Acad Ophthalmol Otolaryngol1968; 72:830-48. 4. Mortada A. Clinical characteristics of early orbital metastatic neuroblastoma. Am J Ophthalmol1967; 63:1787-93. 5. Albert DM, Rubenstein RA, Scheie HG. Tumor metastasis to the eye. II. Clinical study in infants and children. Am J Ophthalmol 1967; 63:727-32. 6. Apple DJ. Metastatic orbital neuroblastoma originating in the cervical sympathetic ganglionic chain. Am J Ophthalmol 1969; 68:1093-5. 7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81. 8. Gehan EA. A generalized Wilcoxon test for comparing arbitrarily singlycensored samples. Biometrika 1965; 52:203-23.
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9. Giles CL, Henderson JW. Horner's Syndrome: an analysis of 216 cases. Am J Ophthalmol1958; 46:289-96. 10. Maurer HM. Current concepts in cancer. Solid tumors in children. N Engl J Med 1978; 299:1345-8. 11. The Staff of the Royal Children's Hospital Melbourne. Tumours of the Adrenal Medulla. In: Jones PG, Campbell PE, eds. Tumours of Infancy and Childhood. London: Blackwell Scientific, 1976; Chapter 18. 12. Beckerman BL, Seaver R. Congenital Horner's syndrome and thoracic neuroblastoma. J Pediatr Ophthalmol Strabismus 1978; 15:24-5. 13. Jaffe N, Cassady R, Petersen R, Traggis D. Heterochromia and Horner syndrome associated with cervical and mediastinal neuroblastoma. J Pediatr 1975; 87:75-7. 14. Solomon GE, Chutorian AM. Opsoclonus and occult neuroblastoma. N Engl J Med 1968; 279:475-7. 15. Sandok BA, Kranz H. Opsoclonus as the initial manifestation of occult neuroblastoma. Arch Ophthalmol 1971; 86:235-6. 16. Wilson LMK, Draper GJ. Neuroblastoma, its natural history and prognosis: A study of 487 cases. Br Med J 1974; 3:301-7. 17. Filler RM, Traggis DG, Jaffe N, Vawter GF. Favorable outlook for children with mediastinal neuroblastoma. J Pediatr Surg 1972; 7:13643. 18. Altman AJ, Baehner RL. Favorable prognosis for survival in children with coincident opso-myoclonus and neuroblastoma. Cancer 1976; 37:846-52. 19. Senelick RC, Bray PF, Lahey ME, et al. Neuroblastoma and myoclonic encephalopathy: two cases and a review of the literature. J Pediatr Surg 1973; 8:623-32. 20. deLorimier AA, Bragg KU, Linden G. Neuroblastoma in childhood. Am J Dis Child 1969; 118:441-50. 21. McFarland J, Sappington SW. A ganglioneuroma in the neck of a child. Am J Pathol 1935; 11 :429-48. 22. Stella JG, Schweisguth 0, Schlienger M. Neuroblastoma; a study of 144 cases treated in the lnstitut Gustav-Roussy over a period of 7 years. Am J Roentgenol Radium Ther Nucl Med 1970; 108:325-32. 23. Willis RA. The Pathology of the Tumours of Children. Edinburgh and London: Oliver and Boyd, 1962; 4. 24. Bothman L, Blankstein SS. The eye in adrenal sympathicoblastoma (neuroblastoma); importance of ocular findings, with first pathologic report of metastasic tumor in choroid. Arch Ophthalmol 1942; 27:746-61. 25. Alia JL, FaciA, Garcia-Julian G, Martinez-Tello A. Anterior chamber metastasis from neuroblastoma. J Pediatr Ophthalmol Strabismus 1982; 19:299-301.