A malignant and metastasizing feline cardiac ganglioneuroma.

In the current study, a case of a cardiac ganglioneuroma with systemic metastases in a cat is described. A 12-year-old male neutered Japanese domestic cat was brought to a veterinary hospital for dysorexia, coughing, vomiting, and diarrhea. Ultrasonography revealed a mass adjacent to the right atrium. The animal died of respiratory failure 1 month after the first visit to the hospital. At necropsy, an oval-shaped white mass 1.5 cm in diameter was observed within the right auricle. Diffusely, the right ventricle was infiltrated and thickened by the neoplastic lesion. Histologically, the mass was composed of 3 types of neoplastic cells: spindle cells, large polygonal cells, and small undifferentiated cells. Immunohistochemically, the neoplasia was positive for neuronal markers such as ßIII tubulin, S-100a, and protein gene product 9.5. Ultrastructurally, the large polygonal cells were characterized by abundant cytoplasm that included compressed Golgi cisternae and rough endoplasmic reticula and abundant intermediate filaments. A discontinuous basement membrane surrounded the spindle cells. Metastatic foci were found in the lungs, kidney, pancreas, urinary bladder, and adrenal glands. The morphological, immunohistochemical, and ultrastructural characteristics of the tumor cells were consistent with those of ganglioneuroma. The tumor was presumed to originate from the intramural parasympathetic ganglia in the right atrium.

Colonic ganglioneuromatosis in a horse.

Ganglioneuromas are complex tumors that arise in peripheral ganglia and are composed of well-differentiated neurons, nerve processes, Schwann cells, and enteric glial cells. The term ganglioneuromatosis (GN) denotes a regional or segmental proliferation of ganglioneuromatous tissue. This report describes an 8-year-old mixed breed horse with GN in a 25-cm segment of small colon. Grossly, the lesion consisted of numerous sessile to pedunculated nodules extending from the serosal surface. Histologic examination revealed the nodules to consist of fascicles of spindle-shaped cells consistent with Schwann cells, clusters of neurons, supporting enteric glial cells, and thick bands of perineurial collagen. Most of the nodules coincided with the location of the myenteric plexus and extended through the outer layer of the tunica muscularis to the serosal surface. Neuronal processes were demonstrated within the lesion with electron microscopy. With immunohistochemistry neurons were positive for neuron specific enolase (NSE) and S-100 and the Schwann cells and enteric glial cells were positive for S-100 and glial fibrillary acidic protein (GFAP). The pathogenesis of GN is poorly understood. GN, although rare, should be included in the differential diagnosis of gastrointestinal tumors in the horse.

Noradrenaline storage function of species-specific protein bodies, markers of monoamine neurons in human locus coeruleus demonstrated by dopamine-beta-hydroxylase immunogold localization.

Our histochemical and ultrastructural studies have identified, in human catecholamine locus coeruleus (LC) neurons, abundant and large spherical protein bodies (PB), containing histone-like, arginine-rich proteins, which originate as dense bodies in mitochondria. This species-specific phenotype in the neurons of man is highly intriguing. In the electron microscope PB are disrupted in LC neurons in depressed individuals, where noradrenaline is known to be reduced. This coincidence of ultrastructure and neurochemistry raises the question whether these bodies could qualify as noradrenaline-storing organelles in the human LC. Our rationale was to examine, in known model tissues that contain catecholamines--sympathetic ganglia and tumors of the autonomic nervous system--if vesicles show the same fine structure and histochemistry as the PB of the human LC. Hence, we selected biopsy tissues of five ganglioneuromas and postmortem tissues of LC from 25 control subjects. Since dopamine-beta-hydroxylase (DBH) is a hallmark of noradrenaline identity and present in dense core vesicles, the investigation of DBH localization with the immunogold method constituted the experiment of choice for this study. Histochemical determinations of arginine with Carmoisine L, and of lipids with Rhodamine B complemented the study of similarities between the PB of the human LC and ganglioneuromas. Our results showed, with the colloidal gold method, that DBH immunogold labeling was localized in the core and in the double membranes of the PB, and also in the adjacent mitochondria. These results indicate that protein bodies (a) are unequivocal storage vesicles of noradrenaline, and (b) derive from regular mitochondria and represent a new phenotype in man, which is probably an evolutionary adaptation of amine-storing organelles.

Intrasellar gangliocytomas associated with acromegaly.

The present study was designed to investigate the immunohistochemical characteristics of gangliocytomas associated with growth hormone (GH)-secreting pituitary adenomas. In our surgical collection of 476 GH-secreting adenoma cases, we examined tumor tissue from 6 patients (1.3%). All 6 patients were women, ranging from 29 to 52 years (mean, 40.3 +/- 9.5 SD) of age. Among 470 patients with GH-secreting adenomas without gangliocytoma, there were 255 female and 215 male patients. The preponderance of female patients with gangliocytomas was striking. Histological examination of the resected specimens showed areas of ganglion cells and adenomatous cells. Ganglion cell lesions were stained positively for synaptophysin (4 of 4; 100%) and neurofilament (4 of 4; 100%) as well as GH-releasing hormone (5 of 6; 83.3%). Subtypes of GH cell adenomas included 4 cases of sparsely granulated type and 2 cases of mixed GH and prolactin (PRL) cell adenomas. Based on these findings, we hypothesized that the intrasellar gangliocytoma promoted the growth of the pituitary adenoma by chronic overstimulation from excess GH-releasing hormone.

Multiple endocrine neoplasia type two B. A case report with light and electron microscopic and immunohistochemical correlation.

PURPOSE: To describe a case of multiple endocrine neoplasia type two B (MEN IIB) where ocular and systemic clinicopathological findings are correlated, in association with light and electron microscopic and immunohistochemical findings. METHODS: A 23-year-old man presented with mucosal neuromas of the lips, tongue and eyelids, a Marfanoid habitus and prominent corneal nerves. These findings led to the diagnosis of multiple endocrine neoplasia type two B. The patient subsequently developed phaeochromocytoma and metastatic medullary thyroid carcinoma (MTC) which led to his demise. Correlation of light and electron microscopic and immunohistochemical findings with the systemic and ocular findings is presented to emphasise the aggressiveness of MTC in MEN IIB. Clinicopathological correlation was obtained by examining the eyes post mortem. RESULTS AND CONCLUSIONS: Three new findings in MEN IIB have been established by this study. The enlarged corneal nerves can now be regarded as ganglioneuromas. Medullary thyroid carcinoma metastases were found in the choroid. Light and electron microscopic examination of the eye showed ganglioneuromas of the nerves in the limbus, trabecular meshwork, uveal tract and posterior ciliary nerves; this finding may account for the glaucoma occasionally seen in patients with MEN IIB.

Comparison of ultrastructural features among neuroblastic tumors: maturation from neuroblastoma to ganglioneuroma.

Neuroblastic tumors have the unique ability to differentiate and mature. This family of tumors is composed of the neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. These tumors are derived from primordial neural crest cells that form the sympathetic nervous system. The purpose of this study was to characterize the ultrastructural features of neuroblastic tumors in a pediatric population. Forty-five neuroblastic tumors (15 neuroblastomas, 15 ganglioneuroblastomas, and 15 ganglioneuromas) were examined using standard transmission electron microscopic techniques. Undifferentiated neuroblastomas were composed of primitive cells with rare neurite-like processes containing clear secretory vesicles and no Schwann cell differentiation. Poorly differentiated and differentiating neuroblastomas showed more frequent neuritic processes with infrequent dense core granules and infrequent immature Schwann-like cells. Ganglioneuroblastomas possessed an admixture of cell types, including immature ganglion cells without associated satellite cells, intermediate cells, and differentiating neuroblasts. The neuropil contained immature Schwann cells encasing haphazardly arranged neuritic processes. Ganglioneuromas were composed of mature ganglion cells with occasional binucleation. The neuropil contained mature Schwann cells with well-organized neuritic processes and abundant collagen deposition. Differentiation or maturation of tumor cells, neuritic processes, and Schwann cells may thus be discerned ultrastructurally in primary neuroblastic tumors in pediatric patients.

Pituitary adenoma with neuronal choristoma (PANCH): composite lesion or lineage infidelity?

Fifteen cases of the rare association of pituitary adenoma and neuronal choristoma (PANCH) were investigated by histology, immunohistochemistry, and electron microscopy. Acromegaly was apparent clinically in 11 patients and was equivocal in 1, and 3 lesions appeared to be nonfunctioning. Histology revealed various proportions of chromophobic PA and nervous tissue consisting of neuronlike cells and neuropil. Immunohistochemistry documented growth hormone (GH) in every PA, including those unassociated with clinical acromegaly. In contrast, the NCH component showed no consistent immunohistochemical profile. Most frequent reactivities were for the pituitary hormone alpha subunit, thyroid-stimulating hormone, and GH, whereas only a few cases displayed scattered positivity for GH-releasing hormone. Low-molecular weight keratin tested positive in PAs and in a few cells and processes of an NCH. A few fibrous bodies were immunoreactive for neurofilament protein. Electron microscopy revealed sparsely granulated GH cell adenoma, neurons, and neuropil. Cells intermediate between PA and neurons were numerous in 1 lesion. The present morphologic findings as well as lack of GH cell hyperplasia and the consistent association of NCH with but one type of PA do not support the causative role of NCH in the initiation of PA, as proposed previously. It appears that NCH is the result of neuronal differentiation within sparsely granulated GH cell adenomas.

Immunohistochemical study in two cases of dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos disease).

We report here immunohistochemical study of two cases of dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos disease) a rare entity which is recently classified as a tumor but which hamartomatous nature is also considered. Dysplastic cells of our cases expressed neuronal markers (synaptophysin and NFP), thus their origin from neurons or neuronal precursor is clearly demonstrated. The exact progenitor cell is, however, unknown. The glial involvement was not easily judged based on our histochemical study. While a few GFAP-immunopositive astrocytes were seen in all specimens, including the recurrence of the first case, they appeared of normal size and non hypertrophic in the second case. Furthermore, they did not much increased in number in the recurrent tumor. Thus, it seems that they are not the primary target for the pathogenetic process, whatever it is, of Lhermitte-Duclos disease.

Parapharyngeal ganglioneuroma. Report of a case diagnosed by fine needle aspiration.

A case of ganglioneuroma presenting in a parapharyngeal location in a 4-year-old girl was subjected to fine needle aspiration cytology. A preoperative diagnosis of ganglioneuroma was subsequently confirmed on histopathologic examination. Only a few reports on the cytologic features of this tumor exist. The importance of considering this diagnosis for a tumor at an unusual site and in an uncommon age group is stressed.

Extra-adrenal pheochromocytoma-ganglioneuroma. A case report.

A case of rare extra-adrenal tumor composed of pheochromocytoma-ganglioneuroma which developed in a 48-year-old Japanese male is reported. Histologically, the tumor contained equal proportion of two distinct patterns, pheochromocytoma and ganglioneuroma. Immunohistochemical examination revealed that pheochromocytoma cells were positive for Leu-7 and ganglion cells in ganglioneuroma were positive for vasoactive intestinal peptide (VIP), respectively. Neuron specific enolase (NSE) was positive in the neoplastic cells of both components, and S-100 protein was also positive in fibers around ganglion cells. Ultrastructural examination revealed that neurosecretory granules were present in the neoplastic cells.

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.

Ganglioneuromas of the thyroid gland in a colony of Sprague-Dawley rats.

Ganglioneuromas of the thyroid gland of Sprague-Dawley rats were found in 7.2% of 698 rats used in two, 2-year oncogenicity bioassays. The incidence of the tumor was unrelated to treatment or sex. Of the 52 ganglioneuromas of the thyroid gland identified in 50 animals, 40 (80%) had coincident C cell proliferations in the same or contralateral lobe. Ganglioneuromas were contiguous or commingled with C cell proliferations in 63.5% of the cases. The ganglioneuromas consisted of large ganglion cells and, in a few cases, cells thought to be less differentiated neuronal precursors, in a matrix of neurites and Schwann cells. They grew, infiltrating and expanding in the thyroid parenchyma, and did not metastasize. Immunohistochemical staining for calcitonin, S-100 protein, and neurofilaments, as well as electron microscopy, were used to further characterize the tumors. The close association of ganglioneuromas with C cell tumors supports the theory of neural crest origin of C cells and provides a parallel to the association of ganglioneuromas and pheochromocytomas in the adrenal medulla. This is the first report of ganglioneuromas occurring in the thyroid gland or occurring as a common entity in any species.

Intestinal ganglioneuromatosis: mucosal and transmural types. A clinicopathologic and immunohistochemical study of six cases.

Six cases of intestinal ganglioneuromatosis (GN) included in this study reveal the occurrence of two morphologic patterns. Transmural GN was characterized by neural hyperplasia in all layers of the bowel wall with predominant involvement of the myenteric plexus. It was found in three patients affected by multiple endocrine neoplasia IIb. Mucosal GN, having predominant involvement of the mucosa without concomitant hyperplasia of the myenteric plexus, was associated with von Recklinghausen's disease, adenocarcinoma of the colon, and multiple adenomas with megacolon in one case each. Clinicopathologic correlations and review of the literature suggest that mucosal GN might represent a distinct entity with a lower morbidity rate than the transmural variant. Immunohistochemical stains reveal considerable heterogeneity. S-100 protein, neuron-specific enolase, and synapto-physin immunostaining followed the distribution of the nervous hyperplasia in the different intestinal layers as identified morphologically and allowed precise determination of the proliferating cells. Increased reactivity for vasoactive intestinal polypeptide, opioid peptides leu-enkephalin and met-enkephalin, and substance P was present in all cases with transmural involvement; mucosal GN showed normal reactivity for opioid peptides and focal increased staining for substance P (one case) and vasoactive intestinal polypeptide (two cases) in the lamina propria. Mild increased immunoreactivity for tyrosine hydroxylase was present in the myenteric plexus of four out of four cases. Histochemical determination of acetylcholinesterase, performed in one case of transmural type, demonstrated hyperplasia of parasympathetic fibers and neurons. Electron microscopic study of another case suggested the presence of several neurotransmitters. These results indicate that the physiopathology of GN is related to a complex hyperplasia of several peptidergic, cholinergic, and probably adrenergic nerve fibers instead of a selective overgrowth of one type of nerve fiber.

Primary cerebral ganglioneurocytoma in an adult.

A case of an unusual cerebral neuronal tumor in a 37-year-old woman is described. A clearly marginated tumor, which was found to occupy the septum pellucidum, genu of the corpus callosum, and right frontal lobe, was composed of ganglionic and small round cells. These two populations of neoplastic cells were both interpreted as being in the advanced stages of neuronal maturation, and the authors thus designated this tumor as a "ganglioneurocytoma." Related nosologic problems on central neuronal tumors and their possible histogenesis are also discussed.

Studies with the Golgi method in central gangliogliomas and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease).

The rapid Golgi method, combined with current optical and electronmicroscopical techniques, was used in three central gangliogliomas and in one dysplastic gangliocytoma of the cerebellum to study the morphology of ganglionic cells. Gangliogliomas were composed of bipolar, fusiform and radiate cells with dense core and clear vesicles in the perikaryon and cellular processes, the number of each cellular type varying from one case to another. These features, together with the fact that isodendritic neurons are considered to be phylogenetically old neurons, suggest that these tumours are composed of "primitive" neurons that are not homogeneous with regard to their morphology. In contrast, ganglionic cells in dysplastic gangliocytoma are huge cells with long, stereotyped neurites that establish unique asymmetric contacts with neighbouring perikarya and neurites by means of claw-shaped processes covered with synaptic buttons. These morphological characteristics are different from those of any other neuron of the CNS.

A case of cerebral composite ganglioneuroblastoma: an immunohistochemical and ultrastructural study.

An unusual cerebral tumor is reported in a 14-year-old boy. On light and electron microscopy, the constituent cells were very complex; the majority of the neoplastic cells were primitive neuroectodermal cells dispersed in myxomatous or fibrous stroma. Neoplastic neuronal cells and hypertrophic astrocytes were also observed in these areas. The neuronal cells showed a continuous spectrum of differentiation from very primitive to mature ganglion cells. Furthermore, the tumor contained a highly cellular discrete area consisting of neuroblasts and their precursor cells. From these findings, a diagnosis of composite ganglioneuroblastoma was made.

Morphology of experimental tumors of the sympathetic nervous system.

The morphology of experimental tumors of the sympathetic nervous system in rabbits and hamsters induced by administration of nitrose compounds and the use of modifying factors were studied. The tumors were localized in the mediastinum, retroperitoneal space, adrenals and kidneys. A predominant involvement of the female animals was observed. Histological, histochemical and electron microscopic studies of 33 tumors of the sympathetic nervous system were carried out. By their degree of maturity the tumors were classified as ganglioneuromas, ganglioneuroblastomas and neuroblastomas. By their structure the experimental tumors were similar to the analogous neoplasias of man.

Mixed gangliocytoma-adenoma: a distinct neuroendocrine tumor of the pituitary fossa.

A mixed gangliocytoma-adenoma occurring in the pituitary fossa of a patient who presented with acromegaly, galactorrhea, and headaches is described. Immunohistochemical studies demonstrated the gangliocytic portion of the tumor to be composed nearly entirely of ganglion cells enmeshed in their neuritic processes and disclosed focal presence of growth hormone and prolactin-secreting cells in the adenoma. Ultrastructurally, some of the larger ganglion cells contained (and were often filled with) zebra-like bodies, while the adenoma was shown to be sparsely granulated with numerous fibrous bodies. These findings support the term of mixed gangliocytoma-adenoma for these rare intrasellar tumors and provide additional support for their nature as independent neuroendocrine units.