Unusual clinical behavior of a very late retinoblastoma relapse in a patient with a germline RB mutation

Abstract

To the Editor: Retinoblastoma is the most common pediatric intraocular malignancy with survival rates exceeding 95% utilizing therapies, including systemic chemotherapy, intra-arterial chemotherapy, and local therapies (e.g., focal laser), and in advanced cases, eye enucleation.1,2 High-risk features for extra-ocular spread include tumor invasion of the postlaminar optic nerve, choroid, anterior segment or sclera with relapses occurring typically within 2 years of diagnosis.1,3,4 We report a patient with bilateral intraocular retinoblastoma who suffered a systemic relapse after a long-term remission (Figure S2). At the age of 2 months, he was diagnosed with group B (International Intraocular Retinoblastoma Classification [IIRC]) bilateral retinoblastoma harboring a germline intronic RB1 mutation (Table S1). He was treated on the Children’s Oncology Group (COG) ARET0331 protocol with six cycles of systemic carboplatin, vincristine, and focal laser therapy. Due to disease progression, his right eyewas enucleated at the age of 12 months. Based on the lack of high-risk histopathology, no additional therapy was administered. After 8 years of remission, he presented with vague wrist pain and was found to have minimal soft tissue swelling of the wrist. His complete blood count (CBC) and lactate dehydrogenase (LDH) levels were normal. He was evaluated by rheumatology, diagnosed with idiopathic arthritis and started on naproxen therapy with pain relief. Three months later, he developed worsening leg pain. His physical exam demonstrated a 2 cm left axillary lymph node. His hemoglobin was 10.9 g/dl, platelets 136,000/mm3 and LDH >6000 U/L (undiluted). His bone marrow demonstrated diffuse tumor infiltration by metastatic retinoblastoma confirmed by immunophenotyping and synatophysin staining. Cytogenetics demonstrated an abnormal karyotype including gains of chromosome 1q, 2p, 6p, and 13q32-34. Positron emission tomography-computed tomography (PET/CT) demonstrated diffuse bony disease with liver and axillary lymph node metastases (Figure 1B). Brain/orbits magnetic resonance imaging (MRI) was negative for central nervous system (CNS) involvement. He began treatment following the COG ARET0321 protocol for metastatic retinoblastoma with the intention to ultimately proceed to stem cell transplant. The cycle was complicated by tumor lysis syndrome and acute renal failure requiring hemodialysis. His LDH normalized to 275 U/L after peaking at 22,331 U/L (Figure 1A). Tumor restaging demonstrated no evidence of bonemarrow disease and near resolution of his metastatic disease on PET scan (Figure 1C). Following the third chemotherapy cycle, there continued to be no residual tumor. Stem cell transplantation was postponed due to the development of cisplatin-induced thrombotic microangiopathy (TMA). Eightmonths following his initial relapse, he developed left eye deviation with a right cerebellar mass found on MRI imaging (Figure 1D) (confirmed to be retinoblastoma following a gross total resection) with spinal metastasis. There continued to be nometastatic disease outside the CNS. He received craniospinal proton radiation therapy (40Gy)with daily carboplatin andweekly vincristine,whichwereultimatelydiscontinued due to worsening TMA. Palliative therapy was started, and he expired 4 weeks later due to progressive disease. At autopsy, there was no evidence of disease outside the CNS. Over the past 25 years, four patients at our institution developed metastatic retinoblastoma within 2 years of diagnosis (Table S2). An observational study reported that 402 patients with low-risk features did not develop metastatic disease,9 which makes this case unusual as he had low-risk disease at diagnosis. Themarked LDH level in our patient (Figure S1A) reflected the rapid proliferation of the tumor, which likely contributed to its chemosensitivity, resultant tumor lysis syndrome, and acute renal failure. To characterize the genomic landscape and tumor progression, targeted sequencing was performed on the eye (September 2009), bone marrow (February 2018), and brain (October 2018) (Table S1). The normal deoxyribonucleic acid (DNA) from the eye tissue revealed a germline pathogenic variant in the RB1 gene, and in all three tumors, biallelic inactivation of RB1, acquired by somatic inactivation of the remaining allele through copy-neutral loss of heterozygosity (LOH). A set of high-confidence somatic mutations and copy number changes were present in each of the three tumor samples (Figure 1A, Table S1) Similar to many pediatric neoplasms including retinoblastomas,11–13 the overall somatic mutation burden in these tumors were low and all the mutations were nonrecurrent with unknown functional impact. Copy number analysis of the primary cancer, biopsied in 2009, demonstrated copy neutral LOH of 13q and losses on 3q. Two metastatic samples, biopsied in 2018, shared these events in the primary cancer, with additional gains on chromosomes 1q, 2p, 6p, 12, and 15. The brain biopsy showed further gains of chromosome 19 and copy loss on 17p (Figure 1A). This is consistentwith prior reports of several highly recurrent copy number alterations in retinoblastoma.12,13 One theory to explain tumor dormancy posits that cancer cells may acquire the ability to manipulate the tumor microenvironment and evade the immune system, metastasizing to sanctuary tissues,