Genetic and Histopathological Heterogeneity of Neuroblastoma and Precision Therapeutic Approaches for Extremely Unfavorable Histology Subgroups

Peripheral neuroblastic tumors (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are heterogeneous and their diverse and wide range of clinical behaviors (spontaneous regression, tumor maturation and aggressive progression) are closely associated with genetic/molecular properties of the individual tumors. The International Neuroblastoma Pathology Classification, a biologically relevant and prognostically significant morphology classification distinguishing the favorable histology (FH) and unfavorable histology (UH) groups in this disease, predicts survival probabilities of the patients with the highest hazard ratio. The recent advance of neuroblastoma research with precision medicine approaches demonstrates that tumors in the UH group are also heterogeneous and four distinct subgroups—MYC, TERT, ALT and null—are identified. Among them, the first three subgroups are collectively named extremely unfavorable histology (EUH) tumors because of their highly aggressive clinical behavior. As indicated by their names, these EUH tumors are individually defined by their potential targets detected molecularly and immunohistochemically, such as MYC-family protein overexpression, TERT overexpression and ATRX (or DAXX) loss. In the latter half on this paper, the current status of therapeutic targeting of these EUH tumors is discussed for the future development of effective treatments of the patients.

Retroperitoneal ganglioneuroma with nodal involvement in an adult patient with human immunodeficiency virus: a case report and review of the literature

Background Ganglioneuromas are a benign tumor originating from neural crest cells. As one of the neuroblastic tumors, ganglioneuromas are most common in children, with a mean age at presentation of 7 years. Ganglioneuromas are typically singular in nature, but rarely can present with lymph node involvement and distant metastasis. We present a rare case of a retroperitoneal ganglioneuroma found in a human immunodeficiency virus positive adult, which was complicated by lymph node involvement. This case is notable not only in regard to the age of the patient, but also because of his human immunodeficiency virus positive status and the extension of tumor to lymph nodes. Case presentation A 27-year-old Latino male with history of human immunodeficiency virus presented with a 6-month history of left upper quadrant and epigastric abdominal pain with associated nausea and vomiting. The patient had a computed tomography scan showing a retroperitoneal mass encasing the aorta, celiac axis, and superior mesenteric artery. Core needle biopsy revealed ganglioneuroma. Owing to obstructive symptoms, resection of the mass along with partial gastric resection, partial pancreatic resection, and splenectomy was performed by a multidisciplinary group of surgeons. Pathology results revealed metastatic spread of ganglioneuroma to surrounding lymph nodes. Conclusions Ganglioneuromas are most common in children and very rarely occur in adults. However, it is still important to consider this entity in the differential for patients presenting with suspicious symptoms. While rare, it is essential to consider metastasis in this generally benign disease.

Multiple Immunofluorescence Imaging Analysis Reveals Differential Expression of Disialogangliosides GD3 and GD2 in Neuroblastomas

Background Peripheral neuroblastic tumors (pNTs) are the most common childhood extracranial solid tumors. There are several therapeutic strategies targeting disialoganglioside GD2. Disialoganglioside GD3 has become a potential target. However, the mechanism by which pNTs express GD3 and GD2 remains unclear. We investigated the combined expression status of GD3 and GD2 in pNTs and delineated their clinicopathological values. Methods GD3 and GD2 expression was examined in pNT tissue samples (n = 35) using immunohistochemistry and multiple immunofluorescence imaging. Results GD3 and GD2 expression was positive in 32/35 and 25/35 samples, respectively. Combinatorial analysis of GD3 and GD2 expression in neuroblastoma showed that both were heterogeneously expressed from cell to cell. There were higher numbers of GD3-positive and GD2-negative cells in the low-risk group than in the intermediate-risk ( P = 0.014) and high-risk ( P = 0.009) groups. Cases with high proportions of GD3-positive and GD2-negative cells were associated with the International Neuroblastoma Staging System stage ( P = 0.004), Children’s Oncology Group risk group ( P = 0.001), and outcome ( P = 0.019) and tended to have a higher overall survival rate. Conclusion We demonstrated that neuroblastomas from low-risk patients included more GD3-positive and GD2-negative cells than those from high-risk patients. Clarifying the heterogeneity of neuroblastoma aids in better understanding the biological characteristics and clinical behavior.

Diagnostic Value of Seven Different Imaging Modalities for Patients with Neuroblastic Tumors: A Network Meta-Analysis

Objective. We performed a systematic review and network meta-analysis (NMA) to compare the diagnostic value of seven different imaging modalities for the detection of neuroblastic tumors in diverse clinical settings. Methods. PubMed, Embase, Medline, and the Cochrane Library were searched to identify eligible studies from inception to Sep 29, 2020. Quality assessment of included studies was appraised with Quality Assessment of Diagnostic Accuracy Studies. Firstly, direct pairwise meta-analysis was conducted to calculate the pooled estimates of odds ratio (OR) and 95% confidence interval (CI) of the sensitivity, specificity, NPV, PPV, and DR. Next, NMA using Bayesian methods was performed. The superiority index was assessed to quantify the rank probability of a diagnostic test. The studies performed SPECT/CT or SPECT were analyzed separately from the ones only performed planar imaging. Results. A total of 1135 patients from 32 studies, including 7 different imaging modalities, were eligible for this NMA. In the pairwise meta-analysis, 18F-FDOPA PET/CT had a relatively high value of all the outcomes (sensitivity: 10.195 [5.332–19.493]; specificity: 17.906 [5.950–53.884]; NPV: 16.819 [7.033–40.218]; PPV: 11.154 [4.216–29.512]; and DR 5.616 [3.609–8.739]). In the NMA, 18F-FDOPA PET/CT exhibited relatively high sensitivity in all subgroups (all data: 0.94 [0.87–0.98]; primary tumor: 0.89 [0.53–1]; bone/bone marrow metastases: 0.96 [0.83–1]; and primary tumor and metastases (P + M): 0.92 [0.80–0.97]), the highest specificity in the subgroup of P + M (0.85 [0.61–0.97]), and achieved the highest superiority index in the subgroups of all data (8.57 [1–15]) and P + M (7.25 [1–13]). Conclusion. 18F-FDOPA PET/CT exhibited the best diagnostic performance in the comprehensive detection of primary tumor and metastases for neuroblastic tumors, followed by 68Ga-somatostatin analogs, 123I-meta-iodobenzylguanidine (MIBG), 18F-FDG, and 131I-MIBG tomographic imaging.

Pediatric case of presacral ganglioneuroma: diagnostic considerations and therapeutic strategy

Background Ganglioneuroma (GN) is an uncommon tumor belonging to the neuroblastic tumors group and is often localized in the posterior mediastinum, retroperitoneum, and adrenal gland. Presacral (PS) location is extremely rare. Its management remains a challenge. Case presentation A 4-year-old child presented to our department for an isolated abdominal mass. Para-clinical exams concluded to PSGN. Subtotal surgical excision was performed through an anterior transperitoneal approach. The size of the residual tumor did not progress after the 6-year follow-up period and the patients were asymptomatic. Conclusions GN should be considered in the case of soft tissue presacral masses in pediatrics. Subtotal resection seems sufficient in case of an extension to the sacrum with low morbidity. The residual tumors are still stable and the prognosis seems conserved. Further, long-term follow-up in large studies is needed to confirm these findings.

A Novel Germline Compound Heterozygous Mutation of BRCA2 Gene Associated With Familial Peripheral Neuroblastic Tumors in Two Siblings

ObjectivesTo investigate the genetic variants that are responsible for peripheral neuroblastic tumors (PNTs) oncogenesis in one family case.Materials and MethodsOne family was recruited, including the healthy parents, sister affected by neuroblastoma (NB), and brother who suffered from ganglioneuroma (GN). Whole-genome sequencing (WGS) of germline DNA from all the family members and RNA-seq of tumor RNA from the siblings were performed. Mutants were validated by Sanger sequencing and co-IP was performed to assess the impact of the mutant on chemosensitivity in the SH-SY5Y cell line.ResultsA novel compound heterozygous mutation of BRCA2 was locked as the cause of carcinogenesis. One allele was BRCA2-S871X (stop-gain) from the siblings’ mother, the other was BRCA2-N372H (missense) from their father. This novel compound heterozygous mutations of the BRCA2 gene associated with PNTs by disordering DNA damage and response (DDR) signal pathway. Moreover, chemosensitivity was reduced in the NB cell line due to the BRCA2-N372H mutant.ConclusionIn summary, these results revealed a novel germline compound heterozygous mutation of the BRCA2 gene associated with familial PNTs.

Duodenal Ganglioneuroma: A Rare Tumor Causing Upper Gastrointestinal Bleed

Neuroblastic tumors (NTs) include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma (GN). They are very rare in adults. The Surveillance, Epidemiology, and End Results identified 144 patients ≥20 years old at diagnosis (6.1%) from 1973 to 2002. GNs account for 14% of all localized NT. Since 1957, a total of four cases of GN of the duodenum have been reported. We report a novel case of GN of the periampullary region in the duodenum in a 41-year-old man presenting with chronic upper gastrointestinal bleed. Given the rarity of GNs in this age group and the nonspecificity of radiological features, this diagnosis is often missed until histopathology is done. This may negatively affect the prognosis of an otherwise well-prognosticated disease.