3
E D I T O R I A L
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
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 he association between retinoblastoma and primary intracra-
nial 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 Be-
cause 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, clin-
ical 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 in-
stances, there may even be a complete lack of ocular involve-
ment.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 muta-
tions 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 histopatho-
logic 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 primi-
tive 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 over-
all mortality in hereditary retinoblastoma patients. In bilateral
retinoblastoma patients, the presence of an intracranial malig-
nancy (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 retinoblas-
toma 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 En-
glish 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 im-
portant. 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 develop-
ment 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 retino-
blastoma with an intracranial tumor was more likely
to occur in suprasellar than pineal region tumors.
However, the median survival interval after the diag-
nosis of an intracranial tumor was 6 months, regard-
less 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 obser-
vation (lead time bias, length bias, overdiagnosis bias,
etc.) remains unknown.17 The Children’s Cancer
Group trial regarding prognostic factors for supraten-
torial PNET (unrelated to TRb) reported two indepen-
dent predictors of better outcome: absence of metas-
tases 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 pa-
tients with TRb positively. The location of the intra-
cranial PNET is important because it is a second pre-
dictor of better survival.
Because TRb is nearly always observed in heredi-
tary retinoblastoma (bilateral or multifocal, or a pos-
itive family history), screening efforts should be ap-
plied 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 Pau-
lino,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 diag-
nosis of retinoblastoma. This information is helpful in
designing screening protocols. For prospective screen-
ing for TRb, we currently recommend gadolinium-
enhanced 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 dif-
ferently with various combinations of surgery, che-
motherapy, and radiotherapy including neuraxis ra-
diation. 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 im-
prove in the future.
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