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Mixed pituitary adenoma/PitNET-gangliocytomas (PA/PitNET-GC) have been reported in small series over the past 20 years; some had limited immunohistochemistry (IHC) data. We interrogated our experience over 20 years, focusing on patterns of the GC component and IHC results for anterior pituitary hormones, transcription factors, NFP, and CAM5.2. A search of cases from 2002 to 2023 yielded 20 cases: 7M:13F, ages 20-71 years; 17 macroadenomas, 1 microadenoma, 2 ectopic. GC was co-associated with 4 corticotroph, 2 densely granulated lactotroph, 5 mixed lactotroph-somatotroph, 1 immature PIT1-lineage tumor, and 8 sparsely granulated GH; the latter all had a minor lactotroph component. Patterns were: discrete nodular foci of GC (9/20), extensive GC differentiation often overshadowing the PA/PitNET (7/20), and intimate admixture of smaller bands of neuropil and individual metaplastic ganglion cells within PA/PitNET (4/20). NFP highlighted small cohesive regions of neuropil and identified greater axonal content, including individual axons within "pure" PA/PitNET areas, than appreciated on H&E. CAM5.2 IHC often revealed cells with neuronal morphologies to a greater extent than NFP and in different areas within the same tumor. These data suggest that the combined use of NFP and CAM5.2 IHC best reveals transition from PA to GC phenotype, with CAM5.2 positivity reflecting earlier stages of transformation., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic and mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis of 10 PNTs demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move between adrenergic and mesenchymal cell states via an intermediate state that we term "transitional." Transitional cells express programs linked to a sympathoadrenal development and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature is predictive of poor prognosis compared with adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identifies a similar transitional H3K27-acetylation super-enhancer landscape. Collectively, our study supports the concept that PNTs have phenotypic plasticity and uncovers potential biomarkers and therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Appropriately balanced RET signaling is of crucial importance during embryonic neural crest cell migration, proliferation and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), whereas overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a 'Janus mutation' in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward non-pathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Peripheral sympathetic nervous system tumors are the most common extracranial solid tumors of childhood and include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Surgery is the only effective therapy for ganglioneuroma, which may be challenging due to the location of the tumor and involvement of surrounding structures. Thus, there is a need for well-tolerated presurgical therapies that could reduce the size and extent of ganglioneuroma and therefore limit surgical morbidity. Here, we found that an AKT-mTOR-S6 pathway was active in human ganglioneuroma but not neuroblastoma samples. Zebrafish transgenic for constitutively activated myr-Akt2 in the sympathetic nervous system were found to develop ganglioneuroma without progression to neuroblastoma. Inhibition of the downstream AKT target, mTOR, in zebrafish with ganglioneuroma effectively reduced the tumor burden. Our results implicate activated AKT as a tumorigenic driver in ganglioneuroma. We propose a clinical trial of mTOR inhibitors as a means to shrink large ganglioneuromas before resection in order to reduce surgical morbidity., Competing Interests: Disclosures: T. Tao reported grants from Pediatric Cancer Research Foundation and grants from Rally Foundation for Childhood Cancer Research and the Open Hands Overflowing Hearts during the conduct of the study. H. Shi reported grants from Alex's Lemonade Stand Foundation during the conduct of the study. A.T. Look reported grants from National Institutes of Health during the conduct of the study. No other disclosures were reported., (© 2020 Tao et al.)

Background: The aim of this study was to elucidate the significance of immunohistochemical staining patterns of ALK and GD2 in peripheral neuroblastic tumors with different stages and favorable/unfavorable features. Materials and methods: 32 neuroblastomas, 7 ganglioneuroblastomas, and 1 ganglioneuroma cases were immunohistochemically stained with ALK and GD2, and the expressions were graded and correlated with differentiation, size, and favorable/unfavorable histology. Results: There was no statistically significant correlation between ALK immunopositivity and tumor differentiation or stage. Although there was no statistically significant correlation between GD2 immunopositivity and stage, the intensity and prevalence of GD2 immunostaining were statistically significantly higher in the well differentiated group and in tumors which were smaller than 10 cm. Conclusion: GD2 immunostaining levels correlated with tumor differentiation and size. ALK immunostaining was not related to tumor differentiation or stage.

Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a recently recognized rare neuronal tumor, and its pathogenesis is unclear. We analyzed 7 cases of histologically typical MVNT: 6 were adults (mean age, 43.0 years [range, 23-56 years]) and 1 was a child (age, 10 years). The most common symptoms were seizures (n = 4) and headache (n = 2). The tumors were supratentorial (temporal, 5; frontal lobes, 2) in origin as reported. Vacuolated tumor cells were robustly positive for α-INA and Olig2 and at least partly positive for synaptophysin and MAP2, but negative for Neu-N, nestin and CD34. GFAP and vimentin were expressed in reactive astrocytes but not in tumor cells. Negative results were obtained for p53, IDH-1, BRAF V600E , H3 K27M, EGFR, Lin28A, and L1CAM. ATRX, BRG1, INI-1, and TMHH were retained. The Ki-67 labeling index was very low (<1%), and pHH3 revealed no mitotic figure. Ultrastructural features of tumor cells were comparable with those of immature neuronal cells, with several intracytoplasmic myelin-like autophagosomes and pericellular vacuolization. No IDH1/IDH2 and BRAF V600E mutations were found upon direct sequencing. Whole-exome sequencing revealed FGFR2-ZMYND11 gene fusion in 1 case. After gross total resection, all patients were alive without seizures. There was no tumor recurrence during an average period of 68 months (range, 23-101 months). The analysis of 7 typical cases of MVNT suggested that these lesions may be clonal tumors because FGFR2-ZMYND11 fusion was found (1 case)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Neuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive., Methods: The correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro., Results: Based on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What's more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest., Conclusion: Our findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB.

The aim of this study was to discriminate the children malignant peripheral neuroblastic tumors (PNTs) from those with benign histotype ganglioneuroma (GN) based on clinical and biological characteristics in all PNTs. Four hundred and seventy-six patients were included in this study, containing 345 patients for model development and 131 patients for external validation. Multivariate logistic regression analysis was conducted to select potentially useful characteristics for discrimination of histopathology. External validation was performed for model evaluation. Compared with the main characteristics of GN (85/345, 24.6%), those of malignant PNTs (260/345, 75.4%) showed significant differences. Multivariate analysis was performed to further find the characteristics linked to histopathology. The results indicated that for the patients younger than 49 months, the primary site of adrenal and thoracic, the level of serum neuron-specific enolase (NSE) > 33 ng/mL, and tumor encasing blood vessels were the extremely important discrimination factors of malignant PNTs. The area under the receiver-operating-characteristic of the discrimination model was 0.96. The accuracy rate, sensitivity and specificity were 93.4%, 96.3% and 83.8%, respectively. Meanwhile, the accuracy rate of the external validation from the 131 patients was 97.0%. Overall, histopathologic type of childhood malignant PNTs can be discriminated based on age, primary site, NSE level and the relationship between primary tumor and blood vessels.

Chronic diarrhea in infants is a common condition for addressability to pediatric gastroenterologists. The causes are multiple and the delay in reaching the final diagnosis can lead to complications in the general condition of the child. The purpose of this review is to present the bio-clinical and histogenetic particularities of a rare clinical entity, characterized by tumoral causes of chronic diarrhea. VIPomas are neuroendocrine tumors that autonomously secrete vasoactive intestinal peptide (VIP). Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by VIP-producing tumors only rarely occurs in adult patients with non-pancreatic disease. In pediatric patients, it is extremely rare for a VIPoma to originate in the pancreas; instead, WDHA syndrome is usually associated with VIP-secreting neurogenic tumors involving the retroperitoneum or mediastinum. The majority of VIP secreting tumors in pediatric patients are represented by ganglioneuroblastomas or ganglioneuromas originating in the adrenal medulla or sympathetic neural crest. This syndrome of watery diarrhea associated with hypokalemia and achlorhydria was first described by Verner and Morrison, in 1958, and has been assumed to be due to hypersecretion of VIP. In children, as well as in adult patients, the most likely explanation for persistent secretory diarrhea may be an occult VIPoma. In conclusion, the physicians should be aware that there are some rare tumoral causes of chronic diarrhea, often under-diagnosed. If the diagnosis is not considered, extensive gastrointestinal investigations will be undertaken, delaying the diagnosis and avoidable morbidity will occur.

Introduction: Pituitary gangliocytomas are uncommon neuronal tumours that may present with endocrine disorders, the most frequent being acromegaly caused by growth hormone hypersecretion. Cushing's syndrome is very rarely seen with gangliocytomas., Material and Methods: We report the unique case of a 62 year-old woman whose clinical picture and endocrine testing clearly demonstrated adrenocorticotropin (ACTH)-dependent Cushing's syndrome. Pituitary magnetic resonance imaging showed a 12-mm homogeneous, infra- and retrosellar mass first diagnosed as pituitary macroadenoma. Transsphenoidal surgery was performed and allowed complete resection of the tumour with sparing of normal anterior pituitary. Very low postoperative serum cortisol and ACTH levels were observed in the early postoperative period and the patient is still in remission 18 months after surgery, thus demonstrating that the resected lesion was entirely responsible for the clinical picture., Results: Histological and immunocytochemical analyses demonstrated a benign tumour composed of mature neuronal cells suggestive of a gangliocytoma, expressing both ACTH and corticotropin-releasing hormone (CRH). The tumour was surrounded by a rim of pituitary tissue containing ACTH-producing endocrine cells. Careful analysis of the resected lesion did not reveal any pituitary microadenoma. We search literature for similar cases and retraced only nine cases of gangliocytomas associated with Cushing's syndrome. In most of them, the tumour was combined with either pituitary corticotroph adenoma or hyperplasia., Conclusions: Our case represents a unique case of an infrasellar pituitary gangliocytoma which was able to cause Cushing's syndrome by both direct ACTH production and CRH-induced stimulation of neighbour normal corticotroph cells.

Neuroblastoma is the most common extracranial solid childhood tumor, which is believed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. It was previously shown that cyclin D1 (CCDN1) in pediatric neuroblastic tumors (neuroblastoma, ganglioneuroblastoma, and ganglioneuroma) recapitulates its expression during the development of peripheral sympathetic nervous system (PSNS). In the present study, we performed a microarray analysis in order to evaluate the expression of cyclin D1 in neuroblastoma as compared to ganglioneuroma and ganglioneuroblastoma. We first confirmed that comparable levels of cyclin D1 are present in neuroblastoma and fetal neuroblasts. In addition, we observed that neuroblastoma is associated to significantly higher levels of cyclin D1 as compared to both ganglioneuroma and ganglioneuroblastoma. No differences are instead observable between ganglioneuroblastoma and ganglioneuroma. Finally, bioinformatic analysis of cyclin D1-functionally related genes, identified cyclin D2 as an additional marker/etiopathogenic factor in the development of neuroblastoma., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Colonic diffuse ganglioneuromatosis is a benign neoplastic condition characterized by disseminated, intramural, or transmural proliferation of neural elements involving the enteric plexuses, sometimes associated with von Recklinghausen's disease and other multiple tumor syndromes. Colonic diffuse ganglioneuromatosis is usually large, ranging from 1 to 17 cm, and thus can distort the surrounding tissue architecture as well as infiltrate the adjacent bowel wall. However, colonic diffuse ganglioneuromatosis is an exceptional finding in adults and only individual cases are reported in the literature. Herein, we report two unusual cases of adult patients with colonic diffuse transmural ganglioneuromatosis presenting as a large subepithelial tumor.

Background: Composite pheochromocytoma is a rare pathological condition characterized by elements of both pheochromocytoma and neurogenic tumors. However, detailed clinical outcomes of this tumor have not been fully shown. From 2007 to 2013, we experienced three cases of adrenal composite pheochromocytoma. In this report, we investigate the clinicopathological features of these three cases of composite pheochromocytoma and compare them with previously reported cases., Case Presentations: Cases 1 and 2 were a 29-year-old Japanese woman and a 59-year-old Japanese man, respectively. They underwent laparoscopic left adrenalectomy, and pathological examination revealed composite pheochromocytoma-ganglioneuroma. Case 3 was a 53-year-old Japanese man who had been receiving hemodialysis for 17 years. He underwent laparoscopic right adrenalectomy, and pathological examination revealed composite pheochromocytoma-ganglioneuroblastoma. Although the Ki67-positive rates varied from 1.0 to 6.2% among the three cases, no clinical recurrences occurred. Despite the relatively high rate of Ki67 positivity, complete tumor resection resulted in favorable clinical outcomes., Conclusion: We experienced three cases of adrenal composite pheochromocytoma. Although the clinical findings and treatment outcomes of composite pheochromocytoma were similar to those of ordinary pheochromocytoma, further studies of the biological behavior and genetic profiles of composite pheochromocytoma are necessary to achieve a better understanding of this tumor.

Introduction: Pituitary adenomas with gangliocytic component are rare tumors of the sellar region that are composed of pituitary adenoma cells and a ganglion cell component. Their histogenesis and hence nosology is not yet resolved because of the small number of cases reported and lack of large series in the literature., Methods: Herein we report five cases of pituitary adenoma with gangliocytic component to add knowledge to this rare neoplasm., Results: Three cases are functional mammosomatotroph adenomas, one case is functional sparsely granulated somatotroph adenoma and the other is functional corticotroph adenoma. Gangliocytic component showed immunohistochemical expression of hormones in three cases. The ganglion cells were prolactin immunoreactive in case 1, GH and TSH immunoreactive in case 5 and showed expression of prolactin, TSH, ACTH and FSH in case 4. Three cases had undergone more than one surgery of which two had gangliocytic cells only in the recurrent tumors whereas the third case showed gangliocytic cells only in the initial tumor., Discussion: The cases are discussed with clinical and histological features and a brief review of the literature considering the histogenesis is included.

Primary neurogenic gastrointestinal polyps are encountered relatively frequently in routine pathology practice. They encompass a variety of neoplastic entities with clinical, morphologic, and molecular features that reflect the diversity of neural elements within the gastrointestinal system. Although most are benign and encountered incidentally, accurate diagnosis may have important clinical implications because of the associations of certain neurogenic polyps with familial syndromes or other conditions. We review the pathology of these polyps with an emphasis on the diagnostic challenges that they pose and on newly described subtypes.

Background: Paragangliomas are derived from neurosecretory cells believed to be of neural crest origin. A spinal location of paraganglioma is rare and usually presents as an intradural mass., Patient and Methods: A primary intraosseous paraganglioma of sacrum is extremely unusual, and only 6 cases were reported. In this study, we report a rare case of a 44-year-old man with the complaint of low back pain and lower extremity weakness. Imaging workup, including computerized tomography (CT), and magnetic resonance imaging (MRI) presented an intraosseous sacral lesion with invasion of sacrum in the S1-S3 vertebrae, and extension to L4-L5 spinal canal. The patient underwent subtotal tumor resection, followed by radiation therapy., Results: The morphological and immunohistochemical studies revealed a composite tumor of paraganglioma and ganglioneuroma components, with immunopositivity for cytokeratin., Conclusions: To the best of our knowledge, this is the first report in the literature demonstrating an intraosseous sacral paraganglioma with these 2 pathological features.

Lhermitte-Duclos disease (LDD) is a rare, benign, slow-growing, unilateral mass of the cerebellar cortex. Our case is that of a 71-year-old male with a superior cerebellar lesion consistent with LDD on imaging and Magnetic Resonance Spectroscopy (MRS). It has been reported that MRS can be a valuable diagnostic addition, as it allows for a non-invasive diagnosis and analysis to distinguish a benign lesion, such as an intraparenchymal lesion, and in our case, from a true neoplastic lesion.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a β-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

We report a case of a dopamine-secreting giant primary adrenal ganglioneuroma (GN) in a 29-year-old male patient. Although the patient was clinically silent, the 24-hour urine levels of dopamine, normetanephrine, homovanillic acid and vanillyl mandelic acid were elevated. Abdominal ultrasonography and magnetic resonance imaging showed a large solid tumor with calcifications and a slightly lobular edge on the left adrenal gland. A tumor, 13 x 23 x 25 cm in size, was completely resected without morbidity. A 2-year follow-up with computed tomography showed that the postoperative course of the patient was uneventful.

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.

We report a case of oligodendroglioma showing marked neuronal differentiation, which arose in the right frontal lobe of a 46-year-old woman. The resected tumor was composed of a mixture of oligodendroglioma, gangliocytoma, and neurocytoma areas with predominance of gangliocytoma-like areas. The oligodendroglioma areas showed immunoreactivity for Olig2 and mutant isocitrate dehydrogenase 1 protein, whereas the gangliocytoma and neurocytoma areas were positive for synaptophysin and NeuN. Ki-67 labeling index was approximately 5% to 10% in the oligodendroglioma areas. Molecular cytogenetic analyses demonstrated chromosomal losses of 1p and 19q and a mutation of isocitrate dehydrogenase 1 (G395A, R132H) in both the oligodendroglioma and gangliocytoma areas. These data suggest that this tumor is an oligodendroglioma associated with prominent neuronal differentiation. There seems to be a close relationship between oligodendroglial progenitor cells and neuronal cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4)., Methods: Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses., Results: We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132-240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells., Conclusions: Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.

Ganglioneuromas are rare, benign, well-differentiated, slowgrowing tumors of the sympathetic nervous system, composed of large, mature neurons in a stroma composed of Schwann cells. Ganglioneuromas are derived from the neural crest cells and can arise anywhere from the base of the skull to the pelvis. The pre-sacral area is a very rare location for ganglioneuromas to develop. We describe the case of a 31 year old woman, who was incidentally found to have an abnormal pre-sacral mass. The following work-up, revealed the mass to be growing on imagery (computed tomography and magnetic resonance imagery) and fluorine-18 fluorodeoxiglucose avid. The mass was removed by assisted laparoscopy and was found to be a benign ganglioneuroma. This is the first described case of fluorine-18 fluorodeoxiglucose avid, pre-sacral, benign ganglioneuroma.

Objective: To study the clinicopathologic characteristics of peripheral neuroblastic tumors and to evaluate the prognostic significance of these features., Methods: The clinical and pathologic findings were retrospectively reviewed in 121 cases of peripheral neuroblastic tumor. The clinical outcomes of patients were evaluated. The three-year event-free survival rate was analyzed, with respect to age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index., Results: The median age at diagnosis was 2.7 years; and 96 cases (79.3%) occurred in patients younger than 5 years old. The number of cases in Evan's staging I, II, III, IV and IVs was 24, 39, 24, 29 and 5, respectively. There were 82 cases of neuroblastoma (NB) (including 2 cases of undifferentiated NB, 52 cases of poorly differentiated NB and 28 cases of differentiating NB), 9 cases of ganglioneuroblastoma, intermixed type (GNBi), 19 cases of ganglioneuroma, maturing type (GN) and 11 cases of ganglioneuroblastoma, nodular type (GNBn). Forty-nine cases were in the favorable histology subgroup and 72 cases in the unfavorable histology subgroup. The overall three-year event-free survival rate of the 121 cases was 73.0% ± 4.3%. The three-year event-free survival rates were associated with age (P = 0.002), Evan's staging (P = 0.000), histologic category (P = 0.000), mitosis-karyorrhexis index (P = 0.043), prognostic subgroup (P = 0.000)., Conclusions: Most of the peripheral neuroblastic tumors occur in the children younger than 5 years old. It is composed of NB, GNBi, GN and GNBn. The three-year event-free survival rate is approximately 70%. Significant prognostic parameters include age of patients, Evan's staging, International Neuroblastoma Pathology Classification and mitosis-karyorrhexis index.

A ganglioneuroma is an extremely rare benign neoplasm composed of neural elements, including mature ganglion cells that originate from the sympathetic ganglia. It is located most frequently in the posterior mediastinum and can be found in the retroperitoneum, including the adrenal medulla. It may evolve from a differentiating neuroblastoma or may be diagnosed as a primary ganglioneuroma. Primary orbital ganglioneuromas are extremely rare, with only 2 reported cases in young otherwise-healthy individuals. A single, reported case of bulbar conjunctival ganglioneuromas has been described in water buffalos. This is the first report of a primary subconjunctival ganglioneuroma in a young healthy person.

Aims: More than 50% of neuroblastomas (NBs) present with haematogenous and/or lymphatic metastasis; however, little is known about the clinicopathological significance in NBs of the key lymphangiogenesis growth factors vascular endothelial growth factor (VEGF)-C and VEGF-D and the receptor VEGFR-3., Methods and Results: Ninety-three NBs and nine ganglioneuromas (GNs) were immunostained for VEGF-C, VEGF-D and VEGFR-3. VEGF-C and VEGF-D were present in 76% and 82% of the NBs, respectively. There was no significant difference in VEGF-C expression between NBs and GNs. VEGF-D expression was significantly higher in NBs compared with GNs and in MYCN-amplified NBs. VEGFR-3 tumoral cell expression (VEGFR-3c), present in 48% of the NBs, was significantly higher in NBs from children ≥ 18 months at presentation and those belonging to a high-risk group. VEGFR-3 lymphovascular density was increased significantly in NBs compared with GNs and in NBs associated with adverse clinicopathological and biological factors. Lymphovascular invasion, assessed in VEGFR-3-stained vessels, was present in ∼50% of NBs. Cox regression analyses demonstrated that VEGFR-3c expression was associated with a significantly shorter event-free survival and that its effect was independent of the important pathological variable, mitosis-karyorrhexis index., Conclusions: VEGF-D and VEGFR-3 up-regulation support tumour progression in NB and VEGFR-3c may provide a useful prognostic marker in NBs., (© 2012 Blackwell Publishing Limited.)

Eight cases of ganglioneuroma were examined for a presence of perineural cell differentiation, using the immunohistochemical markers epithelial membrane antigen (EMA), claudin-1 and GLUT-1. The mean age of the patients was 42.3 years (range 26-68 years), six patients were females and two were males. Five tumors were located in the adrenal gland and 3 tumors in the retroperitoneum. Morphology of the tumors was typical, i.e., they were composed of neuroid spindle cell population and scattered mature appearing ganglion cells. Spindle cells positive for perineural cell markers claudin-1 and GLUT-1 were found in all lesions, at least focally. EMA+ cells were seen in 2 of 8 tumors. These perineural-type cells were often arranged in organoid fashion around the schwannoid bundles or around the vessels. Our findings indicate that perineural cell differentiation is commonly present in ganglioneuromas.

Ganglioneuromas are benign tumors originating from the neural crest and are composed of mature ganglion cells. We describe a 15-year-old normotensive adolescent girl with a 2-month history of left flank pain. Imaging revealed a left suprarenal mass with elevated urinary dopamine level. During laparoscopic adrenalectomy, intraoperative rebound hypertension occurred. After resection, dopamine levels normalized. The pathologic diagnosis revealed an adrenal ganglioneuroma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Acromegaly secondary to growth hormone-releasing hormone (GHRH) excess is rare., Aims/case Description: We report two patients with acromegaly who were diagnosed with sellar gangliocytomas that were immunopositive for GHRH. Tumour tissue persisted after debulking surgery and in the second case this was associated with persistent growth hormone hypersecretion, successfully suppressed by a somatostatin analogue., Conclusions: The development of functional pituitary adenomas in association with sellar gangliocytomas is poorly understood. We present a brief discussion of the possible aetiology of these unusual pituitary tumours.

Neuroblastoma (NB) is a challenging problem in oncology, as the majority of patients have lymphatic and/or hematogenous metastases at diagnosis. We investigated the prognostic significance of lymphatic density (LD) and invasion (LI) in NBs using the lymphatic endothelial marker podoplanin (PDPN). A total of 77 neuroblastic tumors and 9 ganglioneuromas (GNs) were immunostained for PDPN using D2-40 antibody. Intratumoral lymphatics were identified in 87% (67/77) of NBs and 7/9 GNs. The LD counts were significantly higher (P<0.01) in NBs (median=19.6, range=0.00 to 89.3) than in GNs (median=10.2, range=0 to 18.7). LI, assessed in D2-40-stained lymphatics, was present in 52/67 (78%) NBs. LDs were significantly higher in NBs from patients with adverse clinical factors (advanced-stage, high-risk group, primary abdominal compared with extra-abdominal sites), biological factors (MYCN amplification, 1p deletion, 17q gain), and distant lymph node metastases. LDs and LI were also significantly higher in NBs belonging to an unfavorable pathology prognostic group and in those with a high mitosis-karyorrhexis index. High LD and the presence of LI correlated with a shorter event-free survival in univariable analyses. High LD and the presence of LI were also associated with worse overall survival, although the association was less strong. In conclusion, increased LDs and the presence of LI correlated with adverse clinicopathologic and biological factors and survival. These findings suggest that PDPN has the potential to provide valuable prognostic information to clinicians for risk assessment in NBs.

An unusual case of ganglioneuroma with perineural cell differentiation is presented. The tumor was removed from the mediastinum in a 34-year-old male patient. Histologically, it contained neuroid bundles of bland spindle cells, scattered ganglion cells, and some foci of adipocytic metaplasia. Immunohistochemically, the tumor showed expected expressions of S100 protein, neurofilament protein and calretinin. In addition, many spindle cells were positive for perineural cell markers EMA, claudin-1, and GLUT-1. These cells were often arranged in an organoid fashion around the schwannoid bundles. This case indicates that the cells of ganglioneuroma can mature simultaneously towards both Schwann cell and perineural cell phenotypes.

Diffuse ganglioneuromatosis of the digestive tract is a rare condition, especially in children. It is frequently associated with multiple endocrine neoplasia type 2b and less commonly with neurofibromatosis type 1 (NF1). We report the case of an 8-month-old baby presenting with vasoactive intestinal polypeptide (VIP)-secreting diffuse ganglioneuromatosis affecting the small intestine and the colon and responsible for severe hydric diarrhea. Postoperatively the infant's symptoms resolved and the serum VIP level was normal. NF1 was clinically suspected and then confirmed through genetic testing. Two years later, the child developed an optic pathway glioma, another tumor frequently associated with NF1., (Copyright © 2012. Published by Elsevier Masson SAS.)

A mass was located in the small intestine of a slaughtered 6-month-old male Landrace-cross pig that had no clinical abnormalities. This egg-shaped well-circumscribed mass was situated in the submucosal and muscular tissue layers and protruded into the lumen. Histopathologically, the tumor comprised discrete or aggregated ganglion and schwannian cells in neuropil-like tissue. Some ganglion cells contained Nissl substance in their cytoplasm. The ganglion cells stained positive for neuron-specific enolase, class III β-tubulin, neurofilament, and synaptophysin; the schwannian cells stained positive for vimentin, S-100 protein, and glial fibrillary acidic protein. The tumor was diagnosed as a ganglioneuroma in accordance with these findings. Here, we have reported detailed immunohistochemical findings in addition to the histopathological features of a swine ganglioneuroma.

Adrenal neoplasms composed of more than one cell type and demonstrating a mixed histologic appearance are exceedingly rare. We report the clinical and pathologic features of a morphologically distinctive tumor of the adrenal gland composed of cortical, chromaffin, and neural cells. Histologically, the tumor consisted of intermixed areas of proliferating cortical cells resembling adrenal cortical adenoma, neoplastic chromaffin cells consistent with pheochromocytoma, and a ganglioneuromatous stroma. The presence of the cortical, medullary, and neural components within the tumor was confirmed by immunohistochemical studies. The present case serves to broaden the morphologic spectrum of mixed tumors that may be encountered in the adrenal gland., (Copyright © 2011 Elsevier Inc. All rights reserved.)

An 11-year-old male Labrador retriever presented with chronic oliguria. Ultrasonography findings revealed a protruding mass at the neck of the urinary bladder. A cystotomy was performed, and the mass was removed by ligation with surgical sutures. Histopathological examination revealed conspicuous foci with a variable number of ganglion cells in the tumor and abundant interwoven bundles of schwannian cells with fine fibers. The ganglion cells were positive for neuron-specific enolase and neurofilament. The schwannian cells were positive for vimentin, S-100 protein, and glial fibrillary acidic protein. Thus, according to the classification of tumor with neuronal cell differentiation, the urinary tumor was diagnosed as a ganglioneuroma.

Background: Adipocytic metaplasia is frequently exhibited by intradermal melanocytic nevi, often in conjunction with melanocytic neurotization, a process termed maturation where melanocytes are assumed to transform to a peripheral nerve phenotype., Objectives and Methods: To present the characteristics of a case of primary cutaneous ganglioneuroma (CGN) with adipocytic metaplasia and compare reported cases of primary acquired CGN with a cohort of neurotized melanocytic nevi (NMN)., Results: We report a case of primary acquired CGN that presented as an asymptomatic, 1-cm, flesh-colored papule on the thigh of a healthy 75-year-old woman. An excisional specimen revealed an intradermal tumor with a dome-shaped profile formed by an intermixed proliferation of ganglion cells, Schwann cells, and numerous adipocytes. Schwann and ganglion cells expressed S100 protein, S100A6, and glial fibrillary acidic protein. Ganglion cells and axonal elements expressed c-kit, synaptophysin, neurofilament, CD56, and neuron-specific enolase. Rare small tumor cells with scant cytoplasm weakly expressed microphthalmia transcription factor protein (Mitf). Similar to NMN, CGN affected the same age group, commonly occurred on the trunk, showed neuromatous differentiation, and in a minority, exhibited adipocytic metaplasia. In contrast, CGNs were significantly larger tumors with more frequent coexisting epidermal changes or desmoplasia. No cases of NMN had authentic ganglion cells, but a minority had ganglion-like cells, which weakly expressed the neural tissue markers c-kit, neuron-specific enolase, CD56, and glial fibrillary acidic protein. A few small Mitf+ cells were found in neuromatous areas and nevic corpuscles of NMN., Conclusions: CGN and NMN are neural crest stem cell-derived tumors that exhibit overlapping and unique phenotypic traits. Adipocytic and neuromatous metaplasia in melanocytic nevi is considered as a consequence of "maturation." Although transformation of an intradermal melanocytic nevus to CGN is a theoretical possibility, the multiple coexisting phenotypes they display most likely arose ab initio in the dermis, mirroring the multiple pathways of differentiation possible for neural crest stem cells. The stage of differentiation of the precursor (stem) cell and interaction with environmental influences most likely predict the final phenotype(s), a pathogenic scheme that better explains the phenomenon of NMN rather than transformation of differentiated melanocyte into a peripheral nerve sheath cell.

Background: Adrenal ganglioneuroma (GN) is seldom considered in the differential diagnosis of adrenal lesions, and its clinical presentation is not well known., Objective: Our aim was to describe the clinical, biochemical, and radiological features of adrenal GNs in adults., Methods: Seven adults underwent endocrine investigation for adrenal lesions that were confirmed to be adrenal GNs., Results: Mean age of the seven patients was 49 yr (range, 23 to 71 yr). Average tumor diameter was 5.0 cm (range, 1.5 to 10.4 cm). In five patients, the adrenal lesions were found incidentally. A 49-yr-old female carried a germline mutation in MSH2 gene. A 57-yr-old female presented with mild virilization and increased testosterone levels. Bilateral adrenal venous sampling revealed testosterone production from her right adrenal lesion. All tumors showed nonenhanced attenuation between 25 and 40 Hounsfield units on computed tomography scan. Magnetic resonance imaging revealed low- to iso-signal intensity on T1-weighted imaging and high-signal intensity on T2-weighted imaging. [(18)F]-2-Fluoro-deoxy-d-glucose-positron emission tomography scan (n = 5) disclosed a mean standard uptake value of 2.4. Three tumors were composite pheochromocytoma-GN. Microsatellite instability study and immunohistochemical analysis of MSH2 protein in a patient carrying a MSH2 mutation showed normal MSH2 protein expression and low microsatellite instability, indicating that the adrenal GN was not related to the patient's MSH2 germline defect., Conclusions: We describe one of the largest series of adult adrenal GNs. Adrenal GNs may secrete testosterone or be part of a composite tumor with pheochromocytoma. The association of adrenal GN with MSH2 mutation seems to be a coincidental finding.

Background: Endoscopic ultrasound-guided fine needle aspiration is a well-established modality in detection and diagnosis of mediastinal lesions. Ganglioneuroma is a benign, rare, soft tissue neoplasm arising from sympathetic ganglion cells, and complete surgical resection is considered to be curative. Ganglioneuroma in a surgical specimen is a straightforward diagnosis; however, due to the infrequent occurrence of this entity, diagnosis by fine needle aspiration is more challenging., Case: A case of paraesophageal ganglioneuroma was diagnosed by endoscopic ultrasound-guided fine needle aspiration. A 75-year-old man with a history of adenocarcinoma of the lung was noted to have a mediastinal mass on chest computed tomography. Upper endosonography identified a 40x17-mm mass extrinsic to the thoracic esophagus. An endoscopic ultrasound-guided fine needle aspiration of the mass revealed intermingled fragments of spindle cells and ganglion cells admixed within a fibromyxoid stroma. Immunohistochemistry showed that both the spindle and ganglion cell components were positive for S-100 protein and negative for pancytokeratin. This immunohistochemical profile established both the neurogenic origin of the spindle and ganglion cells., Conclusion: Our case represents 1 of the few reported cases of ganglioneuroma diagnosed by fine needle aspiration cytology and the second case diagnosed under endoscopic ultrasound guidance.

Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS) that can result in abnormally large enteric neuronal cells (ENCs) in the myenteric plexus and chronic intestinal pseudoobstruction (CIPO). As phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation, and death, we investigated the role of PTEN in the ENS by generating mice with an embryonic, ENC-selective deletion within the Pten locus. Mutant mice died 2 to 3 weeks after birth, with clinical signs of CIPO and hyperplasia and hypertrophy of ENCs resulting from increased activity of the PI3K/PTEN-AKT-S6K signaling pathway. Further analysis revealed that PTEN was only expressed in developing mouse embryonic ENCs from E15.5 and that the rate of ENC proliferation decreased once PTEN was expressed. Specific deletion of the Pten gene in ENCs therefore induced hyperplasia and hypertrophy in the later stages of embryogenesis. This phenotype was reversed by administration of a pharmacological inhibitor of AKT. In some human ganglioneuromatosis forms of CIPO, PTEN expression was found to be abnormally low and S6 phosphorylation increased. Our study thus reveals that loss of PTEN disrupts development of the ENS and identifies the PI3K/PTEN-AKT-S6K signaling pathway as a potential therapeutic target for ganglioneuromatosis forms of CIPO.

Peripheral neuroblastic tumors (PNTs) share a common origin in the sympathetic nervous system, but manifest variable differentiation and growth potential. Malignant neuroblastoma (NB) and benign ganglioneuroma (GN) stand at opposite ends of the clinical spectrum. We hypothesize that a common PNT progenitor is driven to variable differentiation by specific developmental signaling pathways. To elucidate developmental pathways that direct PNTs along the differentiation spectrum, we compared the expression of genes related to neural crest development in GN and NB. In GNs, we found relatively low expression of sympathetic markers including adrenergic biosynthesis enzymes, indicating divergence from sympathetic fate. In contrast, GNs expressed relatively high levels of enteric neuropeptides and key constituents of the Hedgehog (HH) signaling pathway, including Dhh, Gli1 and Gli3. Predicted HH targets were also differentially expressed in GN, consistent with transcriptional response to HH signaling. These findings indicate that HH signaling is specifically active in GN. Together with the known role of HH activity in enteric neural development, these findings further suggested a role for HH activity in directing PNTs away from the sympathetic lineage toward a benign GN phenotype resembling enteric ganglia. We tested the potential for HH signaling to advance differentiation in PNTs by transducing NB cell lines with Gli1 and determining phenotypic and transcriptional response. Gli1 inhibited proliferation of NB cells, and induced a pattern of gene expression that resembled the differential pattern of gene expression of GN, compared to NB (p<0.00001). Moreover, the transcriptional response of SY5Y cells to Gli1 transduction closely resembled the transcriptional response to the differentiation agent retinoic acid (p<0.00001). Notably, Gli1 did not induce N-MYC expression in neuroblastoma cells, but strongly induced RET, a known mediator of RA effect. The decrease in NB cell proliferation induced by Gli1, and the similarity in the patterns of gene expression induced by Gli1 and by RA, corroborated by closely matched gene sets in GN tumors, all support a model in which HH signaling suppresses PNT growth by promoting differentiation along alternative neural crest pathways.

Testosterone secreting tumours of the adrenal glands are usually adrenal carcinomas or adenomas. Here we report the rare case of an adrenal ganglioneuroma with ectopic Leydig cells, a so-called virilizing adrenal ganglioneuroma. Clinically it is characterized by symptoms of virilization, histologically by the occurrence of a population of eosinophilic cells. In the absence of crystalloids of Reinke this cell population can be identified as Leydig cells based on positive immunohistochemical staining of inhibin and calretinin.

Neuroblastoma tumors are derived from the neural crest and exhibit substantial phenotypic heterogeneity and various degrees of differentiation and maturation. The identification of new cell surface markers in neuroblastoma has relevance to disease classification and therapy. As a means to categorize neuroblastomas based on cell surface protein expression, we have obtained a comprehensive profile of the cell surface proteome of the MYCN nonamplified SH-SY5Y neuroblastoma cell line. Biotinylated cell surface proteins were captured using an avidin affinity column, fractionated by reversed-phase chromatography and subjected to in-depth analysis by LC-MS/MS. An extensive list of proteins was established and a subset of surface membrane proteins was assessed by immunohistochemistry in a set of neuroblastoma tissue microarrays. Among identified proteins tested, NCAM and CD147 exhibited increased expression in poorly differentiated tumors (p < 0.01 and <0.03, respectively). CD147 expression was previously associated with aggressive carcinomas but has not been described in neuroblastoma. This comprehensive neuroblastoma cell surface profile has identified novel potential markers for neuroblastoma classification and novel potential targets for therapy.

Watery diarrhoea, hypokalaemia and achlorhydria (WDHA) syndrome was caused by vasoactive intestinal polypeptide (VIP)-producing tumour. A 3-year-old Chinese girl with watery diarrhoea, abdominal distension and hypokalaemia due to a thoracic paraspinal VIP-secreting ganglioneuroma is reported. The girl coughed, fevering up to 39 degrees C after a flu-like episode. She had eight to ten abundant stools daily which is not improved by dietary treatment, resulting in an important weight loss. She weighed 6.8 kg (nl P50 at 6 months of age) and is 76 cm (nl P50 at 9 months of age) in height. Blood electrolytes showed 129 mmol/L sodium, 2.42 mmol/L potassium, 94 mmol/L chloride and 18.6 mmol/L bicarbonate; urinary catecholamines were normal. Computed tomography scan evidenced a left side paravertebral mass of 4 x 6 cm in the lower thoracic region leading to the blood determination of vasoactive intestinal polypeptide which amounted 830 pmol/L(normal < 25 pmol/L). Surgical removal showed a ganglioneuroma of 160 g and was associated with disappearance of the diarrhoea and normalization of VIP level below 20 pmol/L. Review of the 63 reported cases in children with WDHA showed that many of the cases presented with non-treatable watery diarrhoea, hypokalaemia. Achlorhydria is not necessarily part of the WDHA syndrome. The male to female ratio is 1:1.5. Ganglioneuroblastoma and ganglioneuroma are the commonest tumours. Location of the tumour is variable: abdomen, chest or neck. Abdominal distension, flushing, episodic hypertension and colonic dilatation, constipation and ataxia were the other associated features. Surgical resection is the treatment of choice of VIP-producing tumours.