Characterization, treatment and prognosis of retinoblastoma with central nervous system metastasis.

BACKGROUND: Retinoblastoma is the most common primary intraocular tumor and more and more attention has been paid to the developing countries. This study was aimed to evaluate the clinical features, treatment, and prognosis of retinoblastoma patients with central nervous system (CNS) metastasis in Beijing Tongren Hospital, one of the largest tertiary eye centers in China. METHODS: Clinical data of 31 consecutive retinoblastoma patients with CNS metastases, who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between September 2005 and December 2015, were retrospective analyzed. RESULTS: The median age at presentation was 29 months (range from 5 to 108 months). Magnetic resonance imaging (MRI) results indicated that 16 patients (56.6%, 16/31) presented with meningeal involvement, 12 (38.7%, 12/31) presented with intracranial mass, 11 (35.5%, 11/31) presented with thickened optic nerve, and 5 (16.1%, 5/31) presented with concurrent meningeal and spinal cord membrane involvement. Retinoblastoma cells were detected in the cerebrospinal fluid (CSF) of 12 patients (44.4%, 12/27). Laboratory examinations on the blood and CSF were performed for 11 patients who had received six cycles of systemic chemotherapy, indicated that the serum level of neurone-specific enolase (NSE) after chemotherapy was significantly lower than that before chemotherapy (P < 0.05). At the end of the follow-up, 25 patients were dead with a median survival time of 6 months (1 d - 21 months), and 6 cases were alive and continued to receive treatment. CONCLUSION: Our results were basically consistent with previous reports in the developing countries, and it could be guidance for clinical treatment, prognosis and prevention of CNS metastases in retinoblastoma.

Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions.

BACKGROUND: Trilateral retinoblastoma (TRB) is a rare disease associating bilateral retinoblastoma (RB) with primitive intracranial neuroblastic tumor. AIM: To verify the occurrence of TRB in a single-Center case series and point out the clinical relevance of a baseline brain magnetic resonance imaging (MRI) in RB, focusing on pineal gland lesions. PATIENTS AND METHODS: Baseline MRI was routinely performed in all cases of RB from 1999. All MRIs were reviewed for this study and the RB database was checked in order to identify patients characteristics, treatments and follow-up. RESULTS: A total of 107 patients with RB were diagnosed between 1999 and 2012. Sixty-two patients had unilateral RB and 45 bilateral RB. MRI revealed the presence of pineal gland lesions in 10 patients (9%); seven were considered pineal benign cysts (6.5%), while in three patients (2.8%), TRB was suspected. All patients with TRB presented hereditary RB. In one patient, the suspected TRB was metachronous and in the other two patients was synchronous. Biopsy was not performed. Cerobrospinal fluid (CSF) was negative in all patients. The MRI modification, before treatment in the first case and later in the second case, confirmed the TRB diagnosis. The third patient died due to progressive Central Nervous System (CNS) disease that clearly confirmed the TRB diagnosis. None of the three patients had received prior chemotherapeutic treatment. DISCUSSION: TRB represents a rare condition in this series, occurring in three (2.8%) out of all patients with RB. A synchronous presentation with small lesion seems more frequent when a baseline MRI is performed. When a histologically-proven diagnosis is not available, a suspected diagnosis should be considered with caution and only follow-up will confirm the diagnosis. A wait-and-see approach should be considered.

Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA.

AIM: To evaluate minimally disseminated disease (MDD) in cytologically negative cerebrospinal fluid (CSF) specimens of patients with high-risk retinoblastoma by the detection of the synthase of ganglioside GD2 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR). METHODS: The CSF was evaluated in 26 patients with high risk for CSF relapse: 14 with postlaminar optic nerve invasion, five of them with tumour at the resection margin, five with massive choroidal invasion, three with overt orbital extension and four patients with systemic metastasis. Serial CSF examinations were repeated at different time intervals according to stage and in the event of suspected relapse. GD2 synthase mRNA was evaluated by RT and nested PCR at each procedure. RESULTS: MDD was present at diagnosis in six cases (23%) and it was significantly associated to massive optic nerve involvement or history of glaucoma (p<0.05). Three of the children with positive MDD had a CSF relapse. Thirteen patients had negative MDD at diagnosis and one had a CSF relapse. In seven children no ARN could be obtained for PCR analysis and two subsequently relapsed. The probability of CSF relapse was 0.50 (95% confidence interval (CI) 0.13-0.88) for children with MDD and 0.08 (95% CI 0.02-0.46) for those with negative RT-PCR examination of the CSF at diagnosis (p=0.03). CONCLUSIONS: MDD in the CSF detected by RT-PCR for GD2-synthase mRNA occurred in 31.7% of evaluable high-risk children with retinoblastoma with no initial central nervous system (CNS) involvement. It was significantly associated to optic nerve involvement and glaucoma and increased risk of CSF relapse.

Detection of the GD2+/CD56+/CD45- immunophenotype by flow cytometry in cerebrospinal fluids from a patient with retinoblastoma.

Triple-color flow cytometry with a panel of antibodies comprising GD2, CD56, and CD45 was performed to analyze cerebrospinal fluids (CSF) from a patient with retinoblastoma who was suspicious of meningeal metastasis based on clinical presentation. Our results showed that the cells in CSF demonstrated the immunophenotype positive for GD2 and CD56 but negative for CD45 antigen, which suggested the presence of CSF metastasis of retinoblastoma. At the end of eight cycles of intrathecal chemotherapy, CSF specimen was analyzed with Flow cytometry immunophenotyping (FCI) again and the result showed no detectable malignant cells with the same immunophenotype. Our conclusion is that FCI can be a quick and reliable method for the diagnosis of CSF metastasis of retinoblastoma and the immunophenotype (GD2+, CD56+, and CD45-) can be used to recognize residual retinoblastoma cells in CSF.

Bone marrow aspirations and lumbar punctures in retinoblastoma at diagnosis: correlation with IRSS staging.

BACKGROUND: Few studies have suggested that routine bone marrow (BM) and cerebrospinal fluid (CSF) evaluation is not needed in all patients with retinoblastoma. Although the International Retinoblastoma Staging System was developed recently, there remain no clear stage-specific guidelines with regard to the need for BM and CSF evaluations as part of the metastatic workup for patients with retinoblastoma. METHODS: This is a retrospective study analyzing results of CSF cytology and BM evaluation at presentation/diagnosis in patients with retinoblastoma registered at our center from June, 2003 to June, 2009. Only cases with both BM biopsy and lumbar puncture were included. RESULTS: Of the 259 evaluable patients, 18 (7%) were positive for metastasis either in CSF and/or BM. Although 7 of these had overt metastasis at presentation (stage IV), 1 belonged to stage II and 10 to stage IIIa. No stage 0 or I patient tested positive despite presence of histopathologic high-risk factors. CONCLUSIONS: This is the largest study evaluating the role of metastatic workup in patients with retinoblastoma at presentation. We conclude that CSF and BM evaluation is not required in patients with stage 0 and I retinoblastoma at presentation. No definitive recommendation could be made for stage II patients; while stage III and IV patients must certainly be evaluated.

Retinoblastoma CSF metastasis cured by multimodality chemotherapy without radiation.

OBJECTIVE: Cerebrospinal fluid (CSF) metastasis is the most difficult type of retinoblastoma metastasis to cure, even with bone marrow transplant. Most metastatic retinoblastoma cells express P-glycoprotein causing multidrug resistance (MDR). P-glycoprotein-rich blood vessels form blood-brain and blood-eye barriers, inhibit drug entry into central nervous system (CNS) and eyes. High-dose craniospinal radiation is too morbid for treatment of young children. To cure CSF metastasis without radiation, we designed an intensive multimodality chemotherapy regimen. METHOD: After left eye enucleation, a 4-month-old boy with bilateral International Intraocular Retinoblastoma Classification Group E eyes and CSF metastasis was treated with 7-cycle high-dose carboplatin and etoposide, standard-dose vincristine, and high-dose/short-infusion cyclosporine to inhibit P-glycoprotein. Intraventricular drugs, non-substrate of P-glycoprotein (cytarabine), or less susceptible to MDR (topotecan), contributed to treatment of the metastasis. On achieving complete response, he was consolidated with supralethal-dosage carboplatin, etoposide, and cyclophosphamide, and his bone marrow rescued with autologous cord blood stem cells. RESULTS: Following 1-cycle systemic chemotherapy and 2-dose intraventricular chemotherapy, the CSF metastasis cleared. The right eye tumor regressed completely. The patient remains in remission 8.3 years after diagnosis and 7.8 years post-transplant. CONCLUSION: Intensive multimodality chemotherapy can cure CSF metastasis in retinoblastoma without incurring extreme morbidity from craniospinal radiation.

Retinoblastoma with cerebrospinal fluid metastasis treated with orbital and craniospinal irradiation using IMRT.

A 4-year-old male child presented with history of leucocoria, photophobia, and progressive visual deterioration in the left eye. Clinical examination and computed tomography revealed a unilateral retinoblastoma involving the left globe. He underwent enucleation of the left eye and was referred for adjuvant radiotherapy in view of optic nerve infiltration up to the line of resection. However, he did not report for treatment and presented six months later with a recurrent mass in the left orbit with intracranial extension. Cerebrospinal fluid (CSF) cytology was positive for malignant retinoblastoma cells. He received multiagent chemotherapy with vincristine, carboplatin, and etoposide along with intrathecal methotrexate. Although the recurrent orbital mass reduced significantly with chemotherapy, malignant cells persisted in the CSF. He was subsequently treated using intensity modulated radiation therapy (IMRT) to treat the left orbital mass along with craniospinal axis irradiation. Computed tomography done at three and nine months after completion of radiotherapy showed complete disappearance of orbital tumor. CSF cytology also showed no evidence of malignant cells.

Questioning the need for routine bone marrow aspiration and lumbar puncture in patients with retinoblastoma.

PURPOSE: This study assesses the value of routinely investigating children with retinoblastoma with bone marrow aspiration and lumbar puncture, staging investigations not without risk and trauma to the patient, emotional stress on parents and financial cost to the community. METHODS: Medical files and specimens were obtained and examined for patients with retinoblastoma presenting to the Royal Alexandra Hospital for Children, Camperdown and the Children's Hospital at Westmead, Sydney, from 1975 to 2001. RESULTS: In total, 123 patients presented; 62 (50.4%) were boys and 61 (49.6%) were girls. Of these 123 patients, 74 (60.2%) had unilateral disease, 46 (37.4%) involving the left eye and 28 (22.8%) involving the right eye. There were 47 (38.2%) patients with bilateral disease, and two (1.6%) with trilateral disease. Mean age of presentation was 17.9 months (23.1 months for unilateral subjects; 10.3 months for bi-lateral subjects; 3.5 months for trilateral subjects). There were 13 (10.6%) with a positive family history. Of 74 unilateral subjects, 70 (94.6%) required enucleation and four (5.4%) were salvaged. Of 47 bilateral subjects, 13 (27.7%) did not require enucleation, 27 (57.4%) required unilateral enucleation and seven (14.9%) required bilateral enucleation. Both trilateral subjects died. Of all 123 subjects, 112 (91.1%) had bone marrow aspiration and lumbar puncture performed during initial assessment, and none showed evidence of malignancy. CONCLUSIONS: Given the small but significant risks associated with these procedures, the results of this study cannot support bone marrow aspiration and lumbar puncture as routine investigations in all patients presenting with retinoblastoma, suggesting a more limited usage of these investigations is warranted.

[Cerebrospinal fluid cytology in retinoblastoma--possibility of early detection of tumor dissemination into the CNS]. / Cytologie mozkomísního moku u retinoblastomu--moznost vcasného záchytu diseminace nádoru do CNS.

Retinoblastoma is a malignant tumourous which occurs in childhood. The most important factors which influence possible cure of patients with a retinoblastoma are early detection of the disease, correct diagnosis and adequate therapy. In the submitted case-record the authors provide evidence of the importance of cytological examination of cerebrospinal fluid which is important in retinoblastoma in particular for the follow-up of treatment. Cytological examination of cerebrospinal fluid in this type of tumour is very reliable and can reveal infiltration of tumour cells into the CNS much sooner than imaging methods.

Recommendations for the use of routine bone marrow aspiration and lumbar punctures in the follow-up of patients with retinoblastoma.

PURPOSE: Patients with metastatic retinoblastoma have a poor outcome. Hope that early detection of extraocular spread will improve survival has led to routine monitoring with bone marrow and cerebrospinal fluid (CSF) examinations. In light of cost and patient morbidity, the clinical utility of this practice is questioned. PATIENTS AND METHODS: We have performed 254 serial bone marrow aspirations and 164 lumbar punctures in 60 children with retinoblastoma. RESULTS: Two patients with extensive intraocular disease at diagnosis developed positive bone marrow aspirations, although no patient died of distant metastasis. Three patients developed positive CSF examinations. All had neurologic symptoms at the time of CSF positivity. CONCLUSIONS: We recommend performing staging bone marrow and CSF evaluations only in patients with clinical, histologic, or radiologic evidence of local or systemic extension (Pratt stage III-IV), or in patients presenting with one Reese-Ellsworth group V eye and retrolaminar or extrascleral extension of their tumor. We recommend limiting follow-up bone marrow and CSF evaluations to patients who develop objective signs and symptoms of metastatic or regionally recurrent disease.

The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma.

Lumbar punctures (n = 115) and bone marrow aspirations (n = 114) were performed as part of the routine initial diagnostic evaluation of 115 children with retinoblastoma. Three spinal fluid examinations were positive for tumor cells, and bone marrow smears of three children demonstrated clumps of tumor cells. Five of the six positive studies were in patients with stage IV (extraglobar) disease. These results show that demonstrable CSF or bone marrow involvement is so infrequent an event at diagnosis in patients without symptoms, signs, or histologic evidence of tumor dissemination (stages I-II) as to support a recommendation that these studies need not be performed routinely in such patients. If, after enucleation, there is evidence of extraglobar extension, or if patients have symptoms or signs of CNS or systemic spread (stages III or IV), both procedures should be performed to accurately stage disease and provide baseline measurements of tumor involvement for monitoring of response to chemotherapy and/or irradiation. These results have importance in terms of justification of invasive work-up of most (greater than 85%) affected children, and cost containment.

Elevation of cerebrospinal fluid catecholamine metabolites in patients with intracranial tumors of neuroectodermal origin.

The concentrations of homovanillic acid (HVA), hydroxymethoxyphenylethyleneglycol (HMPG), and vanillylmandelic acid (VMA) were determined in lumbar cerebrospinal fluid (CSF) specimens. The study population consisted of the following groups: control subjects with malignancies of nonneuroectodermal origin (mostly leukemia in remission), neuroblastoma (extracranial and intracranial or cranial metastases), brain tumors (neuroectodermal and glial), and retinoblastoma. A significant increase in the CSF concentration of HVA was observed in patients with brain tumors (neuroectodermal), neuroblastoma (intracranial or cranial metastases), and retinoblastoma when compared with age-matched controls. In contrast, HMPG and VMA concentrations did not differ from controls except in patients with neuroblastoma (intracranial or cranial metastases) and brain tumors (neuroectodermal) who had significant elevations in HMPG and VMA, respectively. An inverse correlation was noted between the CSF concentration of HVA and clinical response to therapy. Nonresponding patients exhibited increases in HVA when compared with pretreatment values. These data suggest that the quantitative determination of catecholamine metabolites in lumbar CSF is an effective method for diagnosing intracranial tumors of neuroectodermal origin and assessing their response to therapy.

[Meaning of pleocytosis in spinal fluid in children with neoplasias]. / Significado de la pleocitósis del LCR en niños con neoplasias.

Thirty-five spinal fluids with leucocytosis belonging to 26 children presenting neoplasia without metastases or CNS infection, were studied. We found that 69% of the cases were receiving some kind of CNS therapy, although leucocytosis could be found at any moment of the evolution and independently of treatment. It is stressed that the criteria for meningeal infiltration in children with neoplasia must be established only if tumoral cells are found in the spinal fluid. Pleocytosis and absence of symptomatology must not be used as the main criteria.

Treatment of malignant meningitis in retinoblastoma.

Six patients with meningitis due to retinoblastoma are described. The diagnosis may be suspected on clinical examination but is made by the demonstration of malignant cells in the CSF. These patients have been treated with cranial irradiation together with systemic and intrathecal cytotoxic drugs. There is one survivor. It is suggested that the CSF should be examined in all cases at risk so that the appropriate treatment can be started promptly and thus improve the prognosis.