The Pitfall of Ganglioneuroblastoma-Nodular Diagnosis: Clinical and Imaging Considerations over a Rare Bifocal Sporadic Case

Neuroblastic tumors (NTs) represent the most common extracranial neoplasm occurring in childhood. Although ganglioneuroblastoma intermixed (GNBI) and ganglioneuroma (GN) are classified as very low-risk tumors, neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) may represent a serious risk to survival. Unfortunately, areas of GNBI and GNBN can coexist in the same mass, leading to incorrect risk staging when only biopsy is performed. Herein, we describe a case of multifocal NT (thoracic and abdominal localization) occurring in a 4-year-old male. Different histological subtypes, namely GNBI and GNBN, were revealed in the two lesions. We focus on the difficulties of proper diagnosis and risk stratification, underlining the usefulness of several diagnostic tools for appropriate management and therapeutic choices.

NTs are the most frequent extracerebral solid tumors in patients under 2 years of age and originate from sympathoadrenal lineage of neural crest-derived tissues; they develop most frequently in the abdomen, originating from the adrenal glands or paraganglia, in the thoracic, cervical and pelvic regions. According to the International Neuroblastoma Pathology Classification, four types of NTs are distinguished: NB, GNBN (composite, Schwannian stroma-dominant/stroma-rich and stroma-poor), GNBI (Schwannian stromarich) and GN (Schwannian stroma-dominant) maturing and mature subtypes [1,4].
Of note, GNBI usually has a good prognosis since it tends to differentiate and take on the histological and clinical features of GN, which represent the final stage of tumor maturation. Indeed, it has been hypothesized that "mature" NTs originally derive from a NB that has undergone differentiation and this is also suggested by the significantly higher mean age at diagnosis either in GN or in GNBI. [5][6][7]. GN and GNBI are always classified in the very low-risk group according to INRGSS, regardless of stage and age; treatment is surgical excision, which can be complete or partial [8,9]. Moreover, even in the presence of a neoplasm that is considered unresectable, chemotherapy is not recommended due to demonstrating a poor response with no decrease in tumor volume, and with increased toxicity [6,10]. Although GNBI is considered a benign pathology, it represents a gray area within the category of NTs; obtaining diagnostic certainty is, on the one hand, essential, but, on the other hand, difficult because it does not have radiological, metabolic and biochemical features of unambiguous interpretation. Conversely, GNBN can have a course similar to that of NB, requiring more aggressive therapeutic management. The INRGSS provides guidance for treatment choices based on the definition of different risk classes [11][12][13]; thus, it is crucial to obtain a definite diagnosis. For this reason, a surgical approach is often necessary, although burdened by possible postoperative complications. In fact, the biopsy sample may not be representative of the whole tumor, and the radiological and radiometabolic instrumental investigations do not yet provide diriment information to define a precise diagnosis [10]; for example, GNBN may be coexistent with ganglioneuromatous tissue and the nodular component, which is often necrotic or hemorrhagic, may not exhibit radiotracer uptake, leading to a negative result of 123 I-MIBG scintigraphy. Finally, in large lesions with image-defined risk factors suspected to be GNBI, the dilemma is always whether to confirm the diagnosis with a biopsy that may be not non-representative of the entire tumor or to stress a debulking or major surgery that may present vital risk. Although histology is currently the only certain diagnostic mean in order to obtain the molecular information for prognostic definition, there is much debate about the role that radiological and nuclear medicine investigations might play in the diagnosis and differentiation of benign and malignant NTs [14]. Recently, few authors suggest the fundamental contribution of 18 F-FDG PET being able to suggest NB or nodular variant and useful for subsequent clinical choices, in light of the poor contribution of 123 I-MIBG scintigraphy in which 123 I-MIBG uptake is present in mature as well as immature forms [15,16]. There is a correlation between 18 F-FDG PET findings and disease status of NB which found that 18 F-FDG PET uptake is directly proportional to tumor burden and tumor cell proliferation; therefore, higher values of SUVmax suggest the presence of a NT with unfavorable biological characteristics and worse prognosis [17]. Recently, meta-18F-fluorobenzylguanidine ( 18 F-mFBG) showed promise for future staging and response assessment in NBL, allowing for fast and high-resolution imaging of tumors expressing the norepinephrine transporter [18]. Regarding MRI, reliability of DWI in the differential diagnosis of malignant and benign NT is much discussed and it was observed that lower ADC values are more characteristic of NB/GNBN than GNBI/GNs [14]. In the clinical case we describe, the absence of clinical and biochemical features that would point toward the diagnosis is peculiar; in fact, there is no increase in urinary catecholamines and the lesions show uptake at 123 I-MIBG scintigraphy. In summary, the described case highlights the critical issues associated with the diagnosis of GNBN, which is a NT more similar to NB and a less mature form of GN/GNBI. Its diagnosis can be complex as there are no precise clinical and biochemical features that differentiate it from other NTs, and biopsy may not be representative of the whole tumor. Moreover, the presence of image-defined risk factors (IDRF) discourages aggressive surgery to confirm the histology variant and, considering the favorable GNBI/GNs outcome, the surgical risk may be considered and avoided. Significant progress is being made on the use of 18 F-FDG PET and DWI, which could provide additional information on biological features, which can currently only be confirmed by histological examination but should be suggested by different imaging tools. According to our experience, the 18 F-FDG PET and DWI represent useful tools in "gray zone" GN/GNBI in order to avoid aggressive surgery with potential late sequels.     [2]. In view of the GNBI diagnosis (a low-risk tumor), the critical location of the neoplasms and the total absence of clinically evident symptoms, a watch-and-wait strategy was chosen [1,3].         [2].
NTs are the most frequent extracerebral solid tumors in patients under 2 years of age and originate from sympathoadrenal lineage of neural crest-derived tissues; they develop most frequently in the abdomen, originating from the adrenal glands or paraganglia, in the thoracic, cervical and pelvic regions. According to the International Neuroblastoma Pathology Classification, four types of NTs are distinguished: NB, GNBN (composite, Schwannian stroma-dominant/stroma-rich and stroma-poor), GNBI (Schwannian stromarich) and GN (Schwannian stroma-dominant) maturing and mature subtypes [1,4].
Of note, GNBI usually has a good prognosis since it tends to differentiate and take on the histological and clinical features of GN, which represent the final stage of tumor maturation. Indeed, it has been hypothesized that "mature" NTs originally derive from a    [2].
NTs are the most frequent extracerebral solid tumors in patients under 2 years of age and originate from sympathoadrenal lineage of neural crest-derived tissues; they develop most frequently in the abdomen, originating from the adrenal glands or paraganglia, in the thoracic, cervical and pelvic regions. According to the International Neuroblastoma Pathology Classification, four types of NTs are distinguished: NB, GNBN (composite, Schwannian stroma-dominant/stroma-rich and stroma-poor), GNBI (Schwannian stromarich) and GN (Schwannian stroma-dominant) maturing and mature subtypes [1,4].
Of note, GNBI usually has a good prognosis since it tends to differentiate and take on the histological and clinical features of GN, which represent the final stage of tumor maturation. Indeed, it has been hypothesized that "mature" NTs originally derive from a

Informed Consent Statement:
Written informed consent has been obtained from the patient to publish this paper.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.