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.