3 E D I T O R I A L New Insights into Trilateral Retinoblastoma Arun D. Singh, M.D. Carol L. Shields, M.D. Jerry A. Shields, M.D. Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania. T See referenced original article on pages 135– 41, this issue. Address for reprints: Arun D. Singh, MD, Oncology Service, Wills Eye Hospital, 900 Walnut Street, Philadelphia, PA 19107. Received March 10, 1999; accepted March 17, 1999. © 1999 American Cancer Society he association between retinoblastoma and primary intracranial malignancy first was reported in two patients by Jakobiec et al. in 1977.1 Three years later, Bader et al. reported a series of ten patients with bilateral retinoblastoma and pinealoblastoma.2 Because of the embryologic similarities between the retina and the pineal gland, Bader et al. coined a descriptive term: “trilateral retinoblastoma” (TRb).2,3 Since these reports were published, clinical variations of the classic presentation have been reported.4 It is important to realize that retinoblastoma in the setting of TRb can manifest as unilateral retinoblastoma.5 In fact, one of the originally reported cases had unilateral ocular involvement.1 In rare instances, there may even be a complete lack of ocular involvement.4,5 However, in such atypical cases (“forme fruste”) there is a family history of retinoblastoma.6 In nearly all cases, TRb develops in a subset of retinoblastoma patients harboring germline mutations and manifesting heritable disease (bilateral or multifocal, or a positive family history).4,5 The nature of a primary malignant intracranial tumor also can be varied in its location and histopathologic features.5 The majority of tumors are located in the pineal region but the tumors also can occur in the suprasellar and parasellar regions. The histopathologic appearance of the intracranial component of the TRb is not always that of pinealoblastoma.5 Some authors believe that the tumors comprising the intracranial component of TRb are primitive neuroectodermal tumors (PNET) exhibiting varying degrees of neuronal or photoreceptor differentiation, suggesting an origin from the germinal layer of primitive cells (subependymal plate) rather than the pineal gland.7 The clinical and histopathologic findings indicate that TRb is a heterogeneous entity with expected variations in its clinical course. Recent advances in the treatment of retinoblastoma have led to a reduction in the risk of metastasis with a 5-year cumulative survival rate of 91% in the U.S.8 Second malignant neoplasms and trilateral disease have become the significant contributors of overall mortality in hereditary retinoblastoma patients. In bilateral retinoblastoma patients, the presence of an intracranial malignancy (TRb) has become the most frequent cause of death in the first decade of life, accounting for approximately 50% of all 4 CANCER July 1, 1999 / Volume 86 / Number 1 deaths.9,10 Nevertheless, TRb is a rare entity with an estimated 8 such cases occurring annually in the U.S. (birth rate of 3.9 million per year,11 retinoblastoma frequency of 1 in 15,000 live births12; 40% of retinoblastomas are hereditary,13 and 8% of such patients develop TRb).14 In this issue of Cancer, Paulino collected data from all reports of cases of TRb published in the English language over the last 20 years.15 The data were analyzed statistically to answer the question of whether the location of the intracranial tumor is important. The author observed variations in the clinical presentation of the disease with an earlier onset of TRb observed in patients whose tumors were located in the suprasellar region. The median time interval from the diagnosis of retinoblastoma to the development of a tumor in the pineal region was 24 months whereas it was only 1 month for tumors developing in the suprasellar region. Unilateral intraocular retinoblastoma with an intracranial tumor was more likely to occur in suprasellar than pineal region tumors. However, the median survival interval after the diagnosis of an intracranial tumor was 6 months, regardless of the tumor location. In addition, Paulino noted that observations of longer survival times in patients whose intracranial tumors were detected before the onset of related symptoms4,16 compared with those patients whose tumors were diagnosed after the onset of symptoms were indeed statistically significant (P 5 0.002). Whether the observed difference in survival is due to the impact of early treatment or an artifact of observation (lead time bias, length bias, overdiagnosis bias, etc.) remains unknown.17 The Children’s Cancer Group trial regarding prognostic factors for supratentorial PNET (unrelated to TRb) reported two independent predictors of better outcome: absence of metastases and pineal location.18 These findings, when extrapolated to patients with PNET related to TRb, support the view that the detection and treatment of PNET prior to the onset of symptoms (at a presumed premetastatic stage) should impact the survival of patients with TRb positively. The location of the intracranial PNET is important because it is a second predictor of better survival. Because TRb is nearly always observed in hereditary retinoblastoma (bilateral or multifocal, or a positive family history), screening efforts should be applied to the at-risk cohort.10 Although 15% of all unilateral cases of retinoblastoma are hereditary (even in the absence of a positive family history),13 including such patients in screening would only dilute the yield because TRb is 100 times less common in patients with unilateral retinoblastoma.4 In the review by Paulino,15 the median age at the time of diagnosis of a retinoblastoma was 6 months with a median time interval between that diagnosis and the diagnosis of TRb of 21 months. Approximately 90% of patients developed TRb within 4 years of the time of the diagnosis of retinoblastoma. This information is helpful in designing screening protocols. For prospective screening for TRb, we currently recommend gadoliniumenhanced magnetic resonance imaging or computed tomography with contrast every 6 months up to the age of 5 years in patients with hereditary cases of retinoblastoma. The data presented in the article by Paulino15 have been derived from patients treated in different institutions, from many countries, and over a period of 20 years. Not surprisingly, they were treated differently with various combinations of surgery, chemotherapy, and radiotherapy including neuraxis radiation. Survival was dismal in the majority of the cases with only 4 children surviving . 2 years. The cause of treatment failure was tumor dissemination along the neuraxis in approximately 50% of the cases. With the availability of newer chemotherapy regimens, the prognosis of TRb patients may improve in the future. REFERENCES 1. Jakobiec FA, Tso MOM, Zimmerman LE, Danis P. Retinoblastoma and intracranial malignancy. Cancer 1977; 39:2048 –58. 2. 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