Discussion
RB is the most common intraocular malignancy in infancy and childhood.
Recently, more patients have achieved long-term survival. We searched
PubMed, Ovid, and MEDLINE using the terms “RB, hepatic metastasis,”
“RB, liver metastasis,” “RB, hepatic metastases,” “RB, liver
metastases,” but no relevant articles were found. Only one article on
metastatic RB mentioned cases of hepatic metastasis, but it did not
include a detailed description and analysis.7 We
describe a series of rare hepatic metastatic RB cases to provide
pediatric oncologists and ophthalmological oncologists with a deeper
understanding of the biological diversity of RB, which is useful in the
comprehensive evaluation of the patients.
The common symptoms of RB include leukocoria, strabismus, visual loss,
ocular swelling, exophthalmos, etc. In this study, three patients had
periorbital neoplasms, which corresponded to the severity and stage of
the primary tumor. Only one patient with terminal-stage disease had
hepatomegaly (Fig. 2).
As the liver receives an abundant double blood supply from the hepatic
artery and portal vein, it is a common metastatic site for many
malignant tumors.12 However, hepatic metastasis is
rare in RB. In this study, all patients had severe disease with multiple
system involvement, including the CNS, bone marrow, bone, and lymph
nodes. CNS and bone metastases occurred in all the patients (Table 1).
Therefore, we believe that hepatic metastasis from RB occurs in the
advanced stage when several organs and systems are involved, including
the liver. The liver is neither the only metastatic site nor a
susceptible organ for RB.
High-risk pathological factors of RB include invasion of the optic nerve
posterior to the ethmoid plate (including optic nerve stumps) and
extensive invasions of the choroid, sclera, anterior chamber, iris, and
ciliary body.13 These factors are related to a high
risk for metastasis and dissemination. Only three of the patients in
this study underwent enucleation, and each had extensive invasions of
the choroid (Table 3). We infer that hepatic metastasis might occur in
the course of spread through the choroid. However, due to our study’s
limited sample size, there is need for further evidence-based
verification of the correlation between hepatic metastasis and extensive
invasions of the choroid.
NSE is an important indicator of neurogenic tumors.14In all five patients, NSE levels were elevated significantly at the time
of hepatic metastasis diagnosis, which was consistent with distant
metastasis. After chemotherapy, NSE levels decreased in four patients,
while exophthalmos was relieved, and the periorbital neoplasm shrank.
NSE levels remained high in one patient with end-stage disease, who died
1 month after diagnosis of hepatic metastasis. However, NSE levels are
generally elevated in patients with distant metastasis; therefore, it
could not be used as a diagnostic index for patients with RB showing
hepatic metastases.
AFP is synthesized by the liver and is closely related to primary liver
malignancies; however, AFP levels are often normal in patients with
hepatic metastases.15 AFP was measured in three
patients in this study, and the values were within the normal range. We
also analyzed biochemical indicators of liver metabolism (Table 4). We
found elevated LDH levels, but they could be associated with extensive
metastasis and a high tumor burden. Considering the high sensitivity and
poor specificity of LDH, it cannot be used as a tumor marker for hepatic
metastasis from RB.
Imaging methods for diagnosing hepatic metastases include ultrasound,
abdominal CT, and PET-CT.16–18 Imaging findings vary
considerably among patients. They could involve low-density foci on CT
(due to the lack of blood supply to metastases) and intratumoral
necrosis. All the CT studies in this series showed hepatic metastases
with low-density lesions; some were diffuse, while some were isolated,
and some cases involved multiple foci, while others involved single
foci. Calcification was obvious in the tumor in one patient and was even
more obvious after treatment. This reminds us of the characteristic
calcified plaques of intraocular lesions of RB; whether they are related
or not needs further verification.
The prognosis of RB with distant metastasis is poor, especially when the
CNS is involved.5, 19- 20 All the patients had CNS
metastases, from which two died, one had disease progression, and the
other two achieved partial remission and underwent active treatment.
Considering CNS involvement, the prognosis is not good. However, in
terms of hepatic metastases only, four of the five patients achieved
partial remission after chemotherapy, while one showed no response to
treatment. Two patients died, and one showed disease progression. The
causes of death and disease progression were not hepatic metastases.
Therefore, we speculate that chemotherapy is effective for hepatic
metastases, and hepatic metastasis is not a direct cause of death.
The prognosis of patients with RB having hepatic metastases is worse
than that of patients with RB having other metastases, including
metastases in the bone marrow, bone, and lymph nodes. However, this may
be because hepatic metastasis occurs in the end-stage period and with
CNS involvement. To an extent, this also confirms that CNS involvement
is a very important prognostic factor.
To conclude, hepatic metastasis of RB is rare, occurs as distant
metastases, and usually occurs with CNS and bone metastases. Systemic
assessment is necessary in extensive metastasis, and abdominal CT can be
helpful in screening for hepatic metastasis, which is characterized by
low-density lesions with calcification. Presently, NSE, AFP, and LDH
cannot be used as tumor markers for early detection of RB hepatic
metastasis. In future, we need to look for appropriate indicators.
Aggressive chemotherapy may be effective in controlling the progression
of hepatic metastases, but the prognosis is poor, due to multiple organ
metastases, especially CNS metastases. However, hepatic metastasis is
not a direct cause of death. We should focus on looking for an effective
treatment for RB with CNS metastases.