Adrien Latgé1, Séverine Brillouet2,3, Laurent Guillon4, Marion Gambart5, Mehdi Ahmed Krim1, Delphine Vallot6, Frédéric Courbon1,3,7 and Lavinia Vija Racaru1,3,7*
Received: May 31, 2023; Published: June 09, 2023
*Corresponding author: Lavinia VIJA RACARU, Nuclear Medicine Department, ONCOPOLE Claudius Regaud, avenue Irène Joliot Curie, Toulouse, France
High-risk and refractory neuroblastomas carry poor overall survival, and novel approaches must be explored to improve global outcome. With better knowledge of underlying molecular patterns and growing radioligand portfolio, nuclear medicine physicians can test new strategies for disease assessment and therapy. For decades, meta-iodobenzylguanidine (mIBG) has been used to evaluate disease extent when coupled with iodine-123 due to the high expression of noradrenaline transporter (NAT) in neuroblastoma cells. In recent years, 68Ga-DOTATOC has emerged as a new PET-CT tool to screen for somatostatin receptor subtype 2 (SSTR-2) overexpression, opening the way to internal radiotherapy mediated by 177Lu-DOTATATE. We report the case of a 6-year-old patient with refractory neuroblastoma and extensive bone involvement after three lines of chemotherapy. Dual exploration with 123I-mIBG scintigraphy and 68Ga-DOTATOC PET-CT was performed to evaluate the more appropriate therapeutic strategy. We observed significant mismatches regarding bone lesions, some overexpressing NAT and/or SSTR-2. This rare presentation highlights the phenotypic heterogeneity of metastases after various lines of chemotherapy. With more than half of lesions with no or weak SSTR-2 expression, 177Lu-DOTATATE internal therapy was ruled out. Further investigations are needed to better comprehend this tumor mismatch and its prognostic implications. Screening of molecular targets using complementary nuclear imaging techniques is an interesting option to guide treatment of refractory neuroblastomas.
Keywords: Neuroblastoma; 123I-mIBG; 68Ga-DOTATOC; PET-CT; Imaging Biomarkers
Neuroblastoma is a severe condition in youth population, affecting mainly children before five and representing up to 10% of solid pediatric tumors . Overall survival remained poor despite significant advances in therapies. Deriving from cells originating from peripheral sympathetic nervous system, this extracranial malignancy is divided into three groups of different prognoses (low- , intermediate- and high-risk groups) according to various criteria (age, stage, molecular patterns). High-risk patients are prone to metastatic osteo medullar spreading. 5-year overall survival can exceed 60% with modern treatment protocols , but the exploration of new diagnostic and therapeutic strategies is needed to reduce the mortality of metastatic children.
During the last decades, neuroblastoma imaging assessment relies primarily on computed tomography (CT) and Magnetic Resonance Imaging (MRI) for local exploration, while iodine-123 meta-iodobenzylguanidine (123I-mIBG) scintigraphy allows for whole-body evaluation. Imaging in neuroblastoma is chosen upon the International Neuroblastoma Response Criteria (INRC) which have been revised in 2017  under the validation of international groups such as International Society of Paediatric Oncology European Neuroblastoma (SIOPEN) group, with dedicated scoring systems for the metastatic spread assessment and for the evaluation of treatment response. The International Neuroblastoma Risk Group (INRG) designed the INRG Staging System (INRGSS) to stratify patients at initial diagnosis prior to treatment.
The high sensitivity of 123I-mIBG to identify both tissue and bone metastases is correlated to the overexpression of noradrenaline transporter (NAT) in neuroblastoma cells, leading to the high uptake of the radiopharmaceutical inside tumor. This exam can also be used to screen patients who may benefit from 131I-mIBG therapy . In addition, it has been shown that neuroblastoma may also express somatostatin receptor subtype 2 (SSTR-2) in up to 90% of neuroblastoma cells [5- 7]. Tumor abundance of somatostatin receptor is currently assessed in nuclear medicine for diagnostic and therapeutic strategies, mainly for mid-gut neuroendocrine malignancies using radiolabeled somatostatin analogues (e.g., 68Ga-DOTATOC for diagnostic and 177Lu-DOTATATE for therapy). Neuroblastoma patients with high levels of SSTR-2 expression on 68Ga-DOTATOC positron emission tomography-computed tomography (PET-CT) may beneficiate from 177Lu-DOTATATE therapy, with recently demonstrated safety on few case reports and clinical trials [8,9].
We present the case of a 6-year-old patient diagnosed with left adrenal neuroblastoma with synchronous plurifocal metastatic bone involvement. Induction chemotherapy was performed using GPOH protocol (six alternating courses, N5 (vindesine, cisplatin, etoposide) and N6 (vincristine, dacarbazine, ifosfamide, doxorubicin) , but disease response was considered insufficient after six months. Consequently, a new induction chemotherapy was initiated with a combination of irinotecan and temozolomide (VERITAS protocol). After three cycles, a dissociated response was observed: partial response of lower limbs and sacrum metastases, and progression of a secondary cranial lesion. Local radiotherapy was performed on the cranial metastasis, and chemotherapy with irinotecan and temozolomide was pursued. After a total of six cycles, progressive disease was confirmed. According to current guidelines, therapeutic strategy was switched to topotecan-cyclophosphamide in combination with dinutuximab (anti-GD2 antibody). Progressive disease was observed after six cycles of the above-mentioned therapy on 123I-mIBG imaging (whole-body SPECT/CT acquisition 20h after 146 MBq of 123I-mIBG administration; VERITON-CT, Spectrum Dynamics Medical, Israel) (Figure 1A).
International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) classification is used for assessing disease extension in neuroblastoma. Scoring is evaluated using the following criteria. Skeleton is divided in 12 anatomical segments with grading related to the involvement of each segment: 0, no lesion; 1: one discrete lesion; 2: two discrete lesions; 3: three discrete lesions; 4: more than three discrete lesions or diffuse involvement below 50%; 5: diffuse involvement between 50% et 95%; 6: whole segment involvement. With 123I-mIBG scintigraphy, a value of 19/72 was reached in this patient, with identification of various bone foci. Ten days later, to assess the feasibility of metabolic radiation therapy using radiolabeled somatostatin analogues, a whole-body 68Ga- DOTATOC PET-CT was performed (Discovery Omni Legend PET-CT system (GE Healthcare), 2-min/FOV) 50 minutes after intravenous administration of 37 MBq of 68Ga-DOTATOC (according to BMI and pediatric guidelines ). SIOPEN scoring reached a value of 34/72 (Figure 1B).
68Ga-DOTATOC PET-CT was indeed able to identify more lesions than 123I-mIBG scintigraphy: e.g., median skull, upper left humerus, distal left femur and right tibia foci. However, some lesions were remarkably visible only on 123I-mIBG scan, with no or very low uptake on 68Ga-DOTATOC PET-CT: e.g., right skull, right humerus, right acetabulum. Consequently, a significant mismatch of bone lesions was identified in this patient (Figures 1C-1H), with suspected underlying tumoral heterogeneity. As there were more than 50% of lesions with weak to moderate SSTR-2 expression and uptake lower than liver, it was decided that the patient should not be treated with 177Lu- DOTATATE.
This case report highlights the tumoral heterogeneity in a patient with refractory neuroblastoma with bone metastases after three lines of chemotherapy. Imaging of both NAT and SSTR-2 receptors allows for extensive knowledge of molecular targets. While 177Lu- DOTATATE internal radiotherapy data remains scarce, there has been several studies assessing the role and the efficacy of 131I-mIBG in the population of refractory neuroblastoma, able to induce disease response in a significant proportion of patients [12-15]. In the past years, 177Lu-DOTATATE has emerged as a new treatment of metastatic but well-differentiated neuroendocrine malignancies, and its effectiveness for disease control has been demonstrated in a large randomized clinical trial . Given the high mortality rate of children with refractory neuroblastoma, there is a need for new therapeutic approaches, and 177Lu-DOTATATE could be an additional line aside chemotherapy, anti-GD2 immunotherapy and 131I-mIBG therapy.
Dual exploration with 123I-mIBG planar scintigraphy and 68Ga- DOTATOC PET maximum intensity projection (MIP) has been performed by Gains and al. in 2020 in a cohort of 42 patients with neuroblastoma (including 13 patients with refractory disease and 26 patients with relapsed disease), to evaluate and compare the distribution of these radiopharmaceuticals . 68Ga-DOTATOC MIP was able to detect pathological foci in all patients (42/42), while 123I-mIBG scintigraphy missed bone and/or soft-tissue disease in 2/42 patients. As 36/42 patients had bone disease, 123I-mIBG scintigraphy was positive for 29/36 patients, thus underperforming 68Ga-DOTATOC MIP having a positivity rate of 35/36, but the difference was nonsignificant (p = 0.07). It is noteworthy that 7/36 patients had positive bone lesions with 68Ga-DOTATOC MIP and negative with 123I-mIBG scintigraphy, while only 1/36 patient had positive bone lesions with 123I-mIBG scintigraphy and negative with 68Ga-DOTATOC MIP. Discordances between the two imaging techniques were observed in 26/42 patients for skeletal disease and 15/42 for soft-tissue disease. Similarly, to our case report, a mismatch in disease extent was observed in 2/42 patients.
In 2018, the same team carried out an analysis of NAT and SSTR-2 immunohistochemical expression in neuroblastoma tissue samples of 75 patients . They reported a marked intensity and heterogeneity regarding the expression of both molecular targets. Moreover, only a weak correlation was seen between the expression of NAT and SSTR-2 (correlation coefficient = 0.23, p = 0.05), including in patients with stage 4 disease. Patients without MYCN amplification seem to have higher SSTR-2 expression, suggesting a more severe disease. It was also highlighted that expression of both NAT and SSTR-2 tend to increase in refractory patients compared to baseline. Increased SSTR-2 expression as assessed by immunohistochemistry seems to be related to lesions that are more aggressive. Finally, no relation to age, sex, stage, or overall survival was found. These data contrast with an earlier study on a cohort of 49 patients suggesting that primary neuroblastoma with high levels of SSTR-2 expression measured by RT-PCR is associated with better cumulative survival .
This case report shows that there is biological heterogeneity in the expression of noradrenaline and somatostatin receptors, so that both imaging methods are complementary and useful to guide on the choice of the most adequate molecular radiotherapy. Heterogeneous clonal evolution related to genomic instability might be responsible for the mismatch seen in this patient. Biopsies and molecular analysis of tumors could be performed to assess molecular profile. It is interesting to notify that this almost complete mismatch between 68Ga-DOTATOC PET and 123I-mIBG scintigraphy is extremely rare. Moreover, these findings suggest that molecular radiotherapy targeting either NAT or SSTR-2 alone may not treat all the disease. Combined treatments with both 131I-mIBG and 177Lu-DOTATATE may have an advantage over either radiopharmaceutical used as a single agent; however, feasibility and safety need to be explored on prospective clinical trials.
We highlight the molecular discordance of NAT and SSTR-2 receptors expression revealed by dual exploration with 123I-mIBG scintigraphy and 68Ga-DOTATOC PET-CT respectively in a patient with neuroblastoma-related extensive bone involvement, thus ruling out internal therapy with radiolabeled somatostatin analogues. This case confirms the phenotypic heterogeneity of metastatic disease and illustrates the importance of comprehensive target screening using nuclear imaging modalities.