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.

Adrenal ganglioneuromas: a retrospective multicentric study of 104 cases from the COMETE network.

OBJECTIVE: Adrenal ganglioneuromas are rare, differentiated, neuroblastic tumors that originate from the peripheral sympathetic nervous system. Because of their rarity, information is limited, derived from small cases series. Our objective was to characterize this tumor and provide help for its management. METHODS: A retrospective multicenter analysis of adrenal ganglioneuromas from 20 French centers belonging to the COMETE network and one Belgian center. RESULTS: Among the 104 cases identified, 59.6% were women (n = 62/104), median age at diagnosis was 29 years, with 24 pediatric cases. 60.6% (n = 63/104) were incidentalomas. Ganglioneuromas were non-secreting tumors in 90.8% of cases (n = 89/98), whereas the preoperative hormonal evaluation was indeterminate for 9.2% of patients (n = 9/98). CT imaging, performed on 96 patients, revealed large tumors (median diameter of 50 mm) with a non-contrast density > 10 Hounsfield units in 98.1% (n = 52/53) and calcifications in 64.6% of cases (n = 31/48). Increased uptake on 123I-MIBG scintigraphy and 18F-FDG-PET/CT was observed in 26.7% (n = 8/30) and 42.2% (n = 19/45) of the tumors, respectively. All 104 patients underwent surgery. No recurrence was observed among the 42 patients who had an imaging follow-up (mean 29.6 months, median 18 months (4-156)). CONCLUSION: Adrenal ganglioneuromas are large tumors, mostly nonfunctioning, without benign imaging features. Although the duration of follow-up was limited in our series, no recurrence was identified. A review of the literature confirms the absence of postoperative recurrence. Based on all available data, in the absence of special circumstances (genetic form, uncertain histological diagnosis), long-term follow-up is not necessary after complete surgery for patients with an adrenal ganglioneuroma.

A radiological and histological comparison of two unusual adrenal incidentalomas.

INTRODUCTION: The increasing use of radiological imaging studies has given rise to 'incidentalomas'. CASE REPORT: We describe two unusual and diverse incidental adrenal gland lesions, an adenomatoid nodule and a mature ganglioneuroma. Both are deemed 'indeterminate' on radiological assessment. On histology, an adenomatoid nodule is composed of variably-dilated thin-walled cysts lined by bland flattened cells and solid areas of tubules lined by eosinophilic cells with plump nuclei and prominent nucleoli. The lining cells are immunoreactive for calretinin and WT1 while negative for CK5/6, ERG and CD31. Mature ganglioneuroma features fascicles of bland spindle cells with intermixed mature ganglion cells disposed within a background myxoid stroma with no immature neuroblastic component. These spindled Schwann cells are S100 positive. DISCUSSION: Both adenomatoid nodule and mature ganglioneuroma are rare benign adrenal tumours that need to be differentiated from other, more common adrenal lesions. The management of adrenal incidentalomas is challenging. Surgical excision is indicated if an adrenal incidentaloma is more than 4 cm in size, shows malignant features on imaging or evidence of hormone excess.

2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors.

The clinical course of neuroblastoma is more heterogeneous than any other malignant disease. Most low-risk patients experience regression after limited or even no chemotherapy. However, more than half of high-risk patients die from disease despite intensive multimodal treatment. Precise patient characterization at diagnosis is key for risk-adapted treatment. The guidelines presented here incorporate results from national and international clinical trials to produce recommendations for diagnosing and treating neuroblastoma patients in German hospitals outside of clinical trials.

Diagnostic Value of Diffusion-Weighted MRI for Tumor Characterization, Differentiation and Monitoring in Pediatric Patients with Neuroblastic Tumors.

Purpose We explored the diagnostic value of diffusion-weighted MRI (DWI) for tumor characterization, differentiation and therapy monitoring in pediatric patients with extracranial neuroblastic tumors. Materials and Methods All 29 patients (14 girls, median age: 3 years) with neuroblastoma (NB, n = 19), ganglioneuroblastoma (GNB, n = 4) and ganglioneuroma (GN, n = 6) who had had at least one in-house DWI examination since 2005 were identified and retrospectively analyzed. Two independent blinded readers measured ADC values (unit: 10-3 mm2/s) and signal intensity ratios (SIRs) of the primary tumor and, if applicable, of the tumor after chemotherapy, metastases and tumor relapse. Results The pre-treatment ADC was 0.90 ±â€Š0.23 in NB/GNB and 1.70 ±â€Š0.36 in GN without overlap between the two entities for both readers, 0.67 ±â€Š0.14 in metastases and 0.72 ±â€Š0.18 in tumor relapse. With chemotherapy, mean ADC increased to 1.54 ±â€Š0.33 in NB/GNB and to 1.23 ±â€Š0.27 in metastases (p < 0.05). The median SIRs of various tumor lesions vs. liver, vs. muscle tissue and vs. adjacent tissue were significantly higher on DWI (range: 2.4 - 9.9) than on ce-T1w (range: 1.0 - 1.8, all p < 0.05). The coefficient of variation (CV) was ≤ 8.0 % for ADC and ≤ 16.4 % for signal intensity data. Conclusion Based on mean ADC, DWI distinguishes between NB/GNB and GN with high certainty and provides plausible quantitative data on tumor response to therapy. Lesion conspicuity, as measured by SIR, is superior on DWI, compared to ce-T1w. DWI as a noninvasive, radiation-free and widely available imaging technique should be an integral part of MR imaging for neuroblastic tumors and should undergo prospective evaluation in multicenter studies. Key Points · DWI reliably distinguishes neuroblastoma/ganglioneuroblastoma from ganglioneuroma, based on the mean ADC.. · DWI provides plausible quantitative data on tumor response to chemotherapy.. · DWI offers highly superior lesion conspicuity compared to contrast-enhanced T1w imaging.. · DWI should be considered a standard for imaging neuroblastic tumors.. Citation Format · Neubauer H, Li M, Müller VR et al. Diagnostic Value of Diffusion-Weighted MRI for Tumor Characterization, Differentiation and Monitoring in Pediatric Patients with Neuroblastic Tumors. Fortschr Röntgenstr 2017; 189: 640 - 650.

Mixed Pituitary Gangliocytoma and Prolactinoma Resistant to the Cabergoline Treatment.

BACKGROUND: A gangliocytoma rarely coexists with a pituitary adenoma in a sellar lesion. Herein, we describe our experience in treating a mixed gangliocytoma and prolactinoma of the pituitary gland. CASE DESCRIPTION: A 16-year-old male presented with severe headache and vomiting. Magnetic resonance imaging showed a large pituitary tumor with hydrocephalus. Because of the increased levels of serum prolactin (PRL), we treated the patient with cabergoline, which decreased the tumor size and improved the hydrocephalus. Six months after the treatment, the tumor began to increase in size, despite the normalization of the PRL level with cabergoline treatment. An endoscopic transsphenoidal resection was performed and the tumor was mostly removed. Microscopic examination of the resected tumor showed a mixture of prototypical pituitary adenoma cells and the proliferation of mature ganglion cells. Immunohistochemistry showed that the ganglion cells were positively stained for synaptophysin, NeuN, and PRL as shown in the adenomatous component. A few cells were immunostained with both PRL and NeuN, and a few cells were immunopositive for nestin, but not PRL or synaptophysin. CONCLUSIONS: Our findings showed the existence of cells that are phenotypically intermediate between ganglion cells and adenoma cells, and the existence of stem cell-like cells, which support the hypothesis that adenoma cells can transform into ganglion cells or that both ganglion and adenoma cells derive from common stem cells. Furthermore, the ganglion cells seemed to grow rapidly and independently of dopamine, which is in contrast to prototypical prolactinoma cells.

[Giant Ganglioneuroma of the Spine and Mediastinum]. / Objemný ganglioneurom pátere a mediastina.

UNLABELLED: The case of a 15-year-old girl with a large ganglioneuroma in the mediastinum and spinal canal is presented. The tumour initially manifested as scoliosis. Its diagnosis was made on the basis of CT scanning and magnetic resonance imaging, and confirmed by thoracoscopic mediastinal biopsy. Radical tumour excision was indicated. The first stage involved removal of the tumour from the spinal canal through a posterior approach, and transpedicular fixation of the spinal column with correction of the curve. At the second-stage procedure, the tumour was removed from the pleural cavity and mediastinum through thoracotomy. At two years after surgery, the spondylodesis was completed with autologous bone grafts that healed within 6 months. At 3-year follow-up the patient was with neither clinical findings, nor subjective complains and imaging methods showed no signs of tumour recurrence. KEY WORDS: ganglioneuroma, scoliosis, correction, thoracotomy, spinal canal, mediastinum.

Treatment and outcome of Ganglioneuroma and Ganglioneuroblastoma intermixed.

BACKGROUND: Ganglioneuroma (GN) and ganglioneuroblastoma intermixed (GNBI) are mature variants of neuroblastic tumors (NT). It is still discussed whether incomplete resection of GN/GNBI impairs the outcome of patients. METHODS: Clinical characteristics and outcome of localized GN/GNBI were retrospectively compared to localized neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) registered in the German neuroblastoma trials between 2000 and 2010. RESULTS: Of 808 consecutive localized NT, 162 (20 %) were classified as GN and 55 (7 %) as GNBI. GN/GNBI patients presented more often with stage 1 disease (68 % vs. 37 %, p < 0.001), less frequently with adrenal tumors (31 % vs. 43 %, p = 0.001) and positive mIBG-uptake (34 % vs. 90 %, p < 0.001), and had less often elevated urine catecholamine metabolites (homovanillic acid 39 % vs. 62 %, p < 0.001, vanillylmandelic acid 27 % vs. 64 %, p < 0.001). Median age at diagnosis increased with grade of differentiation (NB/GNBN: 9; GNBI: 61; GN-maturing: 71; GN-mature: 125 months, p < 0.001). Complete tumor resection was achieved at diagnosis in 70 % of 162 GN and 67 % of 55 GNBI, and after 4 to 32 months of observation in 4 GN (2 %) and 5 GNBI (9 %). Eleven patients received chemotherapy without substantial effect. Fifty-five residual tumors (42 GN, 13 GNBI) are currently under observation (median: 44 months). Five patients (3 GN, 2 GNBI) showed local progression; all had tumor residuals > 2 cm. No progression occurred after subtotal resection. Two patients died of treatment, none of tumor progression. CONCLUSIONS: GN/GNBI account for one quarter of localized NT and differ from immature tumors in their clinical features. Chemotherapy is not effective. Subtotal resection appears to be a sufficient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers - NB97 (NCT00017225; registered June 6, 2001); NB2004 (NCT00410631; registered December 11, 2006).

Long-term follow-up results of the observation program for neuroblastoma detected at 6-month mass screening.

We conducted an observation program of neuroblastoma in infants, detected by mass screening at 6 months of age; we followed up with them for 15 years. No recurrence was observed after disappearance of tumors, and persistent tumors showed no malignant transformation or metastasis. Histology of the resected tumors showed age-related differentiation.

Hormone-secreting large adrenal ganglioneuroma in an adult patient: a case report and review of literature.

BACKGROUND. Ganglioneuromas (GNs) are neural crest cell-derived tumors and rarely occur in the adrenal gland. They are usually asymptomatic and hormonally silent. The majority of cases are detected incidentally during work-up for unrelated conditions. Hormone-secreting pure adrenal GNs in adults are extremely rare. To date, only four cases have been reported in the English literature. CASE REPORT. We describe an adult case of endocrinologically active adrenal GN incidentally diagnosed in a 64-year-old male patient with history of uncontrolled hypertension. On physical examination, he had a blood pressure (BP) of 160/100 mmHg. Abdominal computed tomography and magnetic resonance imaging showed a large solid tumor (8.5 × 7.5 × 7 cm) in the right adrenal gland. Urinary levels of norepinephrine, normetanephrine, vanillylmandelic acid and dopamin were elevated, although urinary level of epinephrine was suppressed. Right adrenalectomy was performed for treatment purposes. The histological diagnosis of the resected tumor was adrenal GN. CONCLUSIONS. Hormone-secreting pure adrenal GN occurs very rarely in adults and preoperative diagnosis is difficult. Adrenal GN may present with hormonal activity such as increased secretion of catecholamines and their metabolites. There are no specific diagnostic signs and symptoms discriminating GN and pheochromocytoma. Therefore, histopathological examination need for a definitive diagnosis of adrenal GN. The prognosis after completed surgical resection without further therapy seems to be excellent. To our knowledge, the present case is the second report that describes hormone-secreting pure adrenal GN in an adult from Turkey in the English literature. We discuss this case and review the literature on this unusual entity.

Diagnosis and treatment of 29 cases of adrenal ganglioneuroma.

AIM: To evaluate diagnosis and treatment experience for adrenal ganglioneuroma and provide data for clinical surgery. PATIENTS AND METHODS: Analysis clinical feature and iconography and endocrine examination and clinical data of 29-cases adrenal ganglioneuroma in our Hospital. RESULTS: Back discomfort in 10 cases and convulsivum dizziness in 6-cases (hypertension in 2 cases), central obesity in 1 case. 12-cases were found by physical examination. 9-cases were diagnosed as adrenal ganglioneuroma and others were diagnosed as adrenal tumor. After operation, all of the cases were diagnosed as adrenal ganglioneuroma by pathology. Beside one patient were still dizzy with BP (blood pressure): 150/95 mmHg, all of patients completly recovered. CONCLUSIONS: For diagnosis on adrenal ganglioneuroma, we should depend on iconography and pathology. The operation is main method and most of patients can be cured.

[Paraneoplastic neurological syndrome in 12 children].

OBJECTIVE: To investigate the basic clinical characteristics of paraneoplastic neurological syndrome (PNS) in children. METHOD: To retrospectively analyze the clinical data of 12 PNS children who were hospitalized in neurology department in Beijing Children's Hospital from 2010 to 2011. Some patients were followed up after surgery. RESULT: In 12 patients with PNS, 11 were male and 1 was female. The mean onset age were (30.5 ± 15.3) months. The mean duration from neurological symptom onset to finding out of tumor was (112.7 ± 154.4) days. The onset of the disease in 2 patients was acute, in 3 was subacute and in the other 7 was chronic (2 of 7 had 2 to 3 relapses). Of 12 patients, 11 had symptoms of ataxia (3 patients also had opsoclonus and myoclonus, OMS), 1 had weakness of limbs at onset and then had ataxia. Nine of 12 patients had surgery, and pathologic diagnosis was neuroblastoma and ganglioneuroma. Six patients were followed-up for 8 to 21 months. One patient had a little improvement and 5 almost recovered. CONCLUSION: The PNS children can have neurological symptoms only at the onset and there were no particular evidence of tumor. It is prone to misdiagnosis. The prognosis of PNS in children was poor.

From glioblastoma to gangliocytoma: an unforeseen but welcome shift in biological behavior.

The prognosis in children harboring a glioblastoma multiforme (GBM) is usually poor. Few GBMs in children, however, seem to respond quite well to adjuvant chemotherapy. The biological basis for such chemotherapy sensitivity remains uncertain. In this paper the authors report the case of a 2-month-old girl with a histologically confirmed GBM (WHO Grade IV) in whom chemotherapy was accompanied by differentiation of the malignant primary tumor into a typical gangliocytoma (WHO Grade I) showing ganglioid differentiation and expression of neuronal markers synaptophysin, neurofilament, and NeuN as well as a low Ki 67/MIB-1 proliferation index. Array-comparative genomic hybridization did not reveal genetic alterations in either specimen. Even though the underlying biological mechanisms remain to be elucidated, closer examination of frequency and prognostic significance of neuronal differentiation in pediatric GBMs within ongoing and future clinical trials may be warranted.

Collision tumor of anaplastic oligodendroglioma and gangliocytoma: a case report.

A 53-year-old woman presented with a rare case of coexistence of anaplastic oligodendroglioma with gangliocytoma manifesting as progressive disturbance of consciousness and left hemiparesis. Magnetic resonance imaging with gadolinium demonstrated the mass lesion consisted of a strongly enhanced area around the middle cerebral artery and less enhanced areas in the right temporal lobe, insula, and basal ganglia. She underwent subtotal resection of the tumor, resulting in improvement of her symptoms. Macroscopic and histological examination showed the tumor consisted of two distinct components, grayish soft tissue and yellowish hard tissue. The former consisted of cells with equal-sized round-to-oval hyperchromatic nuclei and perinuclear halo with microvascular proliferation and necrosis, and the diagnosis was anaplastic oligodendroglioma. The latter consisted of large and dysplastic neurons with marked nucleoli and basophilic cytoplasm containing Nissl bodies, with nonneoplastic glial cells in the stroma, and the diagnosis was gangliocytoma. Both lesions were distinct, but intermingled at the border. These two tumors apparently occurred as a collision tumor.

[Neuronal tumors: gangliocytoma]. / Tumores neuronales: gangliocitoma.

INTRODUCTION: Gangliocytomas are neuronal tumors of the central nervous system. They tend to appear in children and young adults. These tumors usually appear in the supratentorial compartment in the temporal lobe. Their clinical presentation is frequently as refractory epilepsy. CASE REPORTS: Three gangliocytoma cases in different locations are presented and a review is made. CONCLUSIONS: Immunochemistry is of great value in the pathological study of these lesions, using neuronal markers for the diagnosis. They are usually benign lesions. Therefore, surgical complete removal is the goal to pursue.

An unusual association of a sellar gangliocytoma with a prolactinoma.

The simultaneous occurrence of a hypothalamic and sellar gangliocytoma with a pituitary prolactinoma is very rare. The explanation for such an association is not known. We describe the case of a woman who had a coexisting adjacent pituitary prolactinoma and gangliocytoma within the same sellar mass. The tumor cells of the gangliocytoma demonstrated expression of enkephalin, a product of proopiomelanocortin known to be a prolactin secretagogue. We postulate that in this patient there may be a link between gangliocytoma enkephalin and prolactin hypersecretion.

Malignant ganglioneuroma arising from mediastinal mixed germ cell tumor.

Mixed germ cell tumors with non-germ cell malignant components rarely occur in the anterior mediastinum. We report a case of a 34-year-old man who presented with an anterior mediastinum mass. Mixed germ cell tumor was initially diagnosed based on the pathologic findings of germinoma on thoracoscopic biopsy and clinical findings of elevated serum alpha-fetoprotein and beta-human chorionic gonadotropin. The patient received preoperative chemotherapy and subsequent complete resection of the residual tumor. Pathologic examination of the excised specimen showed predominantly malignant ganglioneuroma and small residual foci of teratoma. To our knowledge, this is the first reported case of a malignant ganglioneuroma arising from mediastinal mixed germ cell tumor.

Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma.

Pheochromocytoma may lead to important emergency situations, ranging from cardiovascular emergencies to acute abdomen and multiorgan failure. It is vital to think about this disease in any emergency situation when conventional therapy fails to achieve control or symptoms occur that do not fit the initial diagnosis. The importance of keeping this diagnosis in minds is underscored by the fact that, in 50% of pheochromocytoma patients, the diagnosis is initially overlooked. Two other tumors of the sympathetic nervous system, neuroblastoma and ganglioneuroma, are less commonly associated with emergency conditions. If they occur, they are often linked to catecholamine excess, paraneoplastic phenomena, or local tumor mass effect.