Congenital malformation syndromes associated with peripheral neuroblastic tumors: A systematic review.

Malformation syndromes with predisposition to peripheral neuroblastic tumors (pNT), including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, may provide clues to critical mutations influencing pNT development. Our objective was to identify and characterize features of pNT associated with specific malformation syndromes. A systematic review of the literature was performed using MEDLINE, Scopus, and Web of Science. We identified 154 of 1014 papers that met eligibility, comprising 207 cases. The patient's age, tumor histology, and frequency of multiple primary tumors varied by malformation syndrome. Genomic studies and systematized reporting are necessary to elucidate cancer risk and the distinct clinical and biological pNT patterns within syndromes.

Appendiceal ganglioneuroma in neurofibromatosis type 2.

Here we report the case of a 30-year-old woman with a history of neurofibromatosis type 2 (NF2) who presented with an incidentally discovered pelvic mass on an ultrasound. The identity of the mass remained indeterminate following a CT and MRI, although appendiceal pathology was suspected. An elective laparoscopy and appendectomy were performed without complication and pathology on the specimen demonstrated an appendiceal ganglioneuroma. To our knowledge, there has been no prior documented case of an appendiceal ganglioneuroma in a patient with NF2. Furthermore, the current case is the first to report the MR characteristics of appendiceal ganglioneuromas.

Radiation-Induced Schwannomas and Neurofibromas: A Systematic Review.

OBJECTIVE: Radiation-induced benign peripheral nerve sheath tumors are uncommon late complications of irradiation. We conducted the largest systematic review of individual patient data. METHODS: We performed a systematic search of PubMed databases and compiled a comprehensive literature review. Kaplan-Meier analysis was used to investigate survival, and statistical significance was assessed with a log-rank test. RESULTS: We analyzed 40 cases of radiation-induced benign peripheral nerve sheath tumors. The histologic distributions were 28 schwannomas, 11 neurofibromas, and 1 ganglioneuroma. The average age of radiation exposure for development of primary lesions was 14.9 ± 15.5 years, and the latency period between radiotherapy to the onset of secondary tumors was 24.5 ± 12.7 years. The average irradiation dose delivered was 26.3 ± 20.3 Gy. The median overall survival for all cases was not reached (95% confidence interval, 22-not reached) months, with 10-year survival rates of 65.2%. Surgical negative margin was a positive prognostic factor for radiation-induced benign peripheral nerve sheath tumors. CONCLUSIONS: The risk of incidence of secondary benign peripheral nerve sheath tumors in patients treated with radiotherapy should be considered in long-term follow-up periods. At present, complete surgical resection is the main stay for the treatment of radiation-induced benign peripheral nerve sheath tumors.

Temporal clustering of neuroblastic tumours in children and young adults from Northern England.

BACKGROUND: The aetiology of neuroblastic tumours is unclear with both genetic and environmental factors implicated. The possibility that an infectious agent may be involved has been suggested. 'Temporal clustering' occurs if cases display an irregular temporal distribution and may indicate the involvement of an agent that exhibits epidemicity. We tested for the presence and nature of temporal clustering using population-based data from northern England. METHODS: We extracted all cases of neuroblastic tumours diagnosed in children and young adults aged 0-24 years during 1968-2011 from the Northern Region Young Persons' Malignant Disease Registry. This is a population-based registry, covering a population of approximately 900,000 young persons, and includes all cases resident in northern England at the time of diagnosis. Tests for temporal clustering were applied using a modified version of the Potthoff-Whittinghill method. Estimates of extra-Poisson variation (ß) and standard errors (SEs) were obtained. RESULTS: 227 cases of neuroblastic tumours were diagnosed during the study period. All the analyses between fortnights and between months found significant extra-Poisson variation, with ß = 0.846 (SE = 0.310, P = 0.004) for the analysis between fortnights within months. Restricting the analyses to the 76 cases diagnosed at ages less than 18 months showed significant extra-Poisson variation between fortnights within months (ß = 1.532, SE = 0.866, P = 0.038), but not between months. In contrast, analyses of cases aged 18 months to 24 years showed significant extra-Poisson variation between quarters within years, as well as over shorter timescales. CONCLUSIONS: Transient environmental agents may be involved in the aetiology of neuroblastic tumours. The initiating factor might be a geographically-widespread agent that occurs in 'mini-epidemics'.

Choroidal ganglioneuroma in a patient with orbitopalpebral neurofibromatosis.

Ganglioneuroma is a rare, benign tumor originating from the sympathetic ganglion cells. Choroidal ganglioneuroma in association with neurofibromatosis type 1 (NF-1) has been reported in a few cases. This study describes a 21-year-old woman with orbitopalpebral NF, who underwent evisceration for pseudophakic bullous keratopathy, intractable glaucoma, and absolute painful eyes and who was found to have choroidal ganglioneuroma and retrobulbar plexiform neurofibroma on histologic examination. This case, together with the previously described cases, suggests that eyes with choroidal ganglioneuromas may have some common clinical and prognostic characteristics, although this condition cannot be diagnosed preoperatively. In patients with NF-1 who may undergo eye removal surgery, the possibility of choroidal tumors should be kept in mind.

MPNST after Radiosurgery: A Report and Review of the Literature.

OBJECTIVE: To report an unusual case of malignant degeneration in a ganglioneuroma of the jugular foramen post stereotactic radiosurgery as well as to systematically review the pertinent literature involving radiosurgery associated malignancies. BACKGROUND: Ganglioneuromas are uncommon lesions of the peripheral nervous system and infrequently reported in the head and neck region. There have been no previously described cases of ganglioneuromas occurring in the jugular foramen. Malignant degeneration of these lesions is rarely described, especially in the context of radiosurgery. Radiosurgery associated malignancies overall are exceptionally rare and only a limited number of cases have been reported. RESULTS/CONCLUSIONS: We describe a case of a ganglioneuroma occurring in the jugular foramen and mimicking the appearance of a jugular foramen schwannoma. This lesion underwent stereotactic radiosurgery and developed a delayed degeneration into a malignant nerve sheath tumor. The occurrence of ganglioneuroma in this region has not been previously described and presumed malignant degeneration is even rarer. This case highlights a previously understated risk associated with stereotactic radiation treatments. To date, 33 previous cases of stereotactic radiosurgery associated malignancies have been reported. We review the pertinent details of these cases. We caution that as follow up periods and awareness increases, reports such as this may become increasingly common.Tumeurs malignes des gaines nerveuses périphériques après la radiochirurgie : à propos d'un cas et revue de littérature.

Ganglioneuroma in the papilla of Vater with neurofibromatosis type 1: report of a case.

Ganglioneuromas (GNs) are rare benign tumors and their association with neurofibromatosis type 1 (NF-1) is especially uncommon. We report in this article the case of a young woman, subjected to diagnostic work-up because of abdominal pain. Endoscopy and histology revealed not only a GN in the papilla of Vater, but also NF-1. Because of the size and macroscopic features of the lesion, we performed pancreatoduodenectomy, from which she recovered uneventfully. Histological examination of the resected tumor confirmed a diagnosis of GN.

Ganglioneuroma in a patient with Turner syndrome.

INTRODUCTION: Ganglioneuroma is a benign neuroblastal tumor that derives from immature cells of the sympathetic nerve system. It is a very rare disease and affects newborns and infants more often than adolescents and adults. The benign tumors are relatively difficult to diagnose since they usually are asymptomatic. We present a case of unusual coincidence of an ganglioneuroma and Turner syndrome (TS). CASE REPORT: An 11.5-year-old TS patient was admitted into the hospital with good general condition. She was 7 months into growth hormone (GH) therapy. The reason for the admission was to carry out control tests. The patient had not complains or abnormalities on physical examination. On the ultrasound examination of the abdomen in the right adrenal area an adrenal tumor was identified. The ultrasound examination of the abdomen performed 13 months earlier did not show any abnormalities. Computed tomography of adrenal glands confirmed right adrenal tumor. The hormonal function of the adrenal gland was normal. The treatment with GH was terminated and the patient was urgently referred to surgical management. The right adrenal gland tumor together with a part of diaphragm was removed. On histopathological examination ganglioneuroma maturum was diagnosed. On the control MIBG examination physiological gaining of tracer in the left adrenal and in the rest tissue in the area of the right adrenal was found. Trepanobiopsy did not confirm neoplastic changes. CONCLUSIONS: There is a necessity of careful monitoring of TS patients also in face of the possibility of disclosure previously not stated neoplasm after starting GH therapy. It is impossible to rule out that GH therapy promote growth of existing neoplasm.

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction.

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.

Ganglioneuroma of the mandible resulting from metastasis of neuroblastoma.

Neuroblastoma, ganglioneuroblastoma and ganglioneuroma are neuroblastic tumours derived from primordial neural crest tissue. The authors report a rare presentation of a ganglioneuroma of the mandible arising from a metastasis of an adrenal neuroblastoma. The pathogenesis and behaviour of ganglioneuromas is discussed, together with recommendations for their management.

Skin abnormalities in individuals with macrocephaly: Cowden disease from a dermatologist's point of view.

Cowden disease is a rare autosomal dominant disorder characterized by multiple hamartomas and (malignant) tumors affecting major organs including the breast, thyroid, endometrium, brain, skin and mucosa. Diagnostic criteria as formulated by the International Cowden Consortium serve as a guideline to clinically identify patients in which Cowden disease is suspected. However, the spectrum of abnormalities associated with PTEN mutations is very broad, such that the term PTEN hamartoma tumor syndrome (PTHS) is often used. The diagnostic criteria for Cowden disease do not always serve to reliably identify patients who fall within the PTHS spectrum. Therefore, it is important that clinicians are aware of features that should raise the suspicion of such a syndrome. To illustrate this point, we present three patients with clinical features of the PTEN hamartoma tumor syndrome spectrum. These patients have macrocephaly in common. Two of them meet the criteria for Cowden disease; one patient refused mutation analysis, while mutation analysis in the other patient revealed no PTEN mutation. The third patient does not meet the criteria for Cowden disease; however, genetic analysis showed a pathogenic mutation in the PTEN gene. Dermatologists regularly encounter the (muco-)cutaneous abnormalities that can be seen in PTEN hamartoma tumor syndrome. These findings combined with a (family) history of internal malignancy or a macrocephaly should raise the suspicion of PTHS, even in the absence of classical Cowden criteria.

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.

Massive spontaneous hemothorax associated with Von Recklinghausen's disease.

A 30-year-old woman with Von Recklinghausen's disease was admitted to our hospital because of sudden onset of dyspnea and syncope. A chest roentgenogram showed a massive right pleural effusion and insertion of an intercostal tube drained 1,600 cc of blood. A computed tomographic chest scan with contrast revealed a hyperdense mass in the right paravertebral area. At thoracotomy, retained clotted hemothorax and continued bleeding from tumor vessels was noted. The apex of the right hemithorax and the tumor location was packed. The pathologic diagnosis was ganglioneuroma and follow-up of the patient for 2 years after re-thoracotomy and removal of the packs revealed no complication and morbidity. We report this case to emphasize the importance of early recognition and prompt surgical intervention in spontaneous hemothorax associated with Von Recklinghausen's disease.

[A case report of Lhermitte-Duclos disease with systematic AVMs].

We report a case of Lhermitte-Duclos disease (LDD) with huge AVMs of left extremities. The patient is a 46-year-old woman, who was identified heart failure due to AVMs at 13 years old and underwent amputation of left arm and several embolizations for AVM of left leg. Following a loss of consciousness, she was admitted to our hospital at 46 years old. CT scan showed a low-density area in the vermis of cerebellum. MR imaging showed a tumor with characteristic parallel linear striation. She was treated with partial resection of tumor. Pathological findings were dysplastic gangliocytoma. She was diagnosed LDD by MR imaging and pathological findings. Some reports describe an association between LDD and Cowden disease. On the other hand, there are reports of an association between Cowden disease and AVM. However, to our knowledge, there is no report of an association between LDD and AVM. Although this case didn't be revealed an association with Cowden disease, we believe that this case is a very interesting one henceforth suggesting the association between LDD, Cowden disease, and AVM.

Ganglion cells in the posterior pituitary: result of ectopia or transdifferentiation?

Histologic examination revealed large ganglion cells within the posterior pituitary of an 80-year-old woman who died of myocardial infarction. Apparently fully mature, the cells were an incidental finding scattered within hyperplastic foci of pars intermedia (PI)-derived cells (basophil invasion) on histologic examination of the pituitary obtained at autopsy. Immunocytochemistry showed staining reactivity for neuron-specific enolase, synaptophysin, alpha subunit of the glycoprotein hormones and beta-endorphin. The presence of these ganglion cells with features similar to those of magnocellular hypothalamic neurons could be considered the result of abnormal migration during the early phase of embryonic life, or differentiation/maturation of neuroblasts, presumed to occur in the embryonic neurohypophysis. Alternatively, transdifferentiation from proliferating PI cells may explain the emergence of neurons; a hypothesis supported by the proximity and shared alpha subunit, and beta-endorphin immunoreactivities of the two cell types.

Cutaneous ganglioneuromas: a case report and review of the literature.

The occurrence of ganglioneuromas outside the sympathetic chains of the mediastinum and abdomen in the nonpediatric age group is rare. We report the case of a solitary cutaneous ganglioneuroma on the abdomen of a 52-year-old woman. The lesion, which had been present for 20 years, measured 1.2 cm in greatest dimension. Unmyelinated axons, Schwann cells, and scattered mature ganglion cells were identified by histochemistry, immunohistochemistry, and electron microscopy. Only three similar cases have been reported in the literature to date. Ganglioneuromas have also been reported as mature components of metastatic neuroblastomas and in association with plexiform neurofibromas, neither of which was present in this case. The pathogenesis of this lesion is unclear, however, aberrant migration of neural crest elements is the most likely explanation. The possible trophic role of sex steroids is also discussed. Although no follow-up series exist, local excision should he curative considering the small size and histologically benign appearance of the lesion.

Cholecystitis, cholelithiasis, and ganglioneuromatosis of the gall bladder: an unusual presentation of MEN type 2b.

A 40 year old man with multiple endocrine neoplasia type 2b (MEN 2b) presented with cholecystitis caused by gall stones. Twenty four years earlier, he had had a partial thyroidectomy for a cold nodule. At his initial presentation MEN 2b with medullary carcinoma of the thyroid had not been made. This was diagnosed while investigating his gall bladder symptoms and he was found to have asymptomatic residual medullary thyroid carcinoma and bilateral adrenal phaeochromocytomas. The cholecystectomy specimen contained several mixed calculi and extensive ganglioneuromatosis with large, prominent nerves containing ganglion cells in the gall bladder wall.