Paraneoplastic cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma.

We describe a case of cerebellar ataxia associated with anti-Hu antibodies and benign ganglioneuroma. A 28-year-old woman developed progressive ataxia with hyporeflexia at the age of 19. Brain MRI showed progressive cerebellar atrophy. Neurophysiological studies, screening of immune-mediated ataxias, oncological markers, vitamin E and genetic tests for spinocerebellar ataxia types 1,2,3, Friedreich ataxia and POLG1 were negative. Anti-Hu antibodies were positive in Western blot and indirect immunofluorescence (1:640). Total-body computed tomography revealed a mediastinum mass; the histological diagnosis was maturing ganglioneuroma. Immunohistochemistry showed a mild reaction between the tumor and the patient's serum, and no reaction between the tumor and control serum. After surgery, serum anti-Hu titer decreased, while ataxic symptoms initially worsened and then stabilized. Ganglioneuroma is a benign tumor, usually derived from the maturation of a neuroblastoma. The benign histology and the presence of anti-Hu antibodies could be related to the positive oncological prognosis and to the slow clinical course mimicking a degenerative ataxia.

Immunohistochemical expression of CD44s in human neuroblastic tumors: Moroccan experience and highlights on current data.

BACKGROUND: Peripheral neuroblastic tumors (pNTs), including neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN), are extremely heterogeneous pediatric tumors responsible for 15 % of childhood cancer death. The aim of the study was to evaluate the expression of CD44s ('s': standard form) cell adhesion molecule by comparison with other specific prognostic markers. METHODS: An immunohistochemical profile of 32 formalin-fixed paraffin-embedded pNTs tissues, diagnosed between January 2007 and December 2010, was carried out. RESULTS: Our results have demonstrated the association of CD44s negative pNTs cells to lack of differentiation and tumour progression. A significant association between absence of CD44s expression and metastasis in human pNTs has been reported. We also found that expression of CD44s defines subgroups of patients without MYCN amplification as evidenced by its association with low INSS stages, absence of metastasis and favorable Shimada histology. DISCUSSION: These findings support the thesis of the role of CD44s glycoprotein in the invasive growth potential of neoplastic cells and suggest that its expression could be taken into consideration in the therapeutic approaches targeting metastases. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1034403150888863

Membranous glomerulonephritis in a patient with an adrenal ganglioneuroma.

Membranous glomerulonephritis has been reported in association with several tumors. This report is the first case of membranous glomerulonephritis associated with an adrenal ganglioneuroma. The sera obtained from the patient at presentation stained the fibrillary component of the ganglioneuroma and the glomerular basement membrane of the kidney. The antibodies present in the patient's serum also reacted with the glomerular basement membrane of several normal and randomly selected abnormal kidneys, including 1 from a patient with Alport's syndrome. The patient's sera contained a circulating tumor antigen-specific antibody that cross-reacted with an antigen present on the podocyte membrane of the renal glomeruli. The resection of the ganglioneuroma resulted in a complete remission of the nephrotic syndrome within months of removal of the tumor. This was associated with loss of antibodies in the patient's serum. The patient was not treated with steroids or any immunosuppressive agents. The patient remains in remission with normal renal function after 9 years of follow-up.

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.

Modulation by interferon alpha of the decreased natural killer activity in patients with glioblastoma.

It is known that natural killer (NK) cells are involved in immunosurveillance against tumours. This study examines the NK activity of mononuclear cells (MNC) from the peripheral blood of patients with glioblastoma. The cytotoxic inducer effect of interferon-alpha (IFN-alpha) upon these MNC has also been studied. A marked decrease in NK activity mediated by MNC from these patients was found. This functional defected in MNC is not due to a decrease in phenotypically defined NK cells. After long-term (5-day) incubation with IFN-alpha, MNC from 5 out of 14 patients showed strong lytic activity against NK-sensitive target cells. In this system, IFN-alpha failed to induce cytotoxic activity against NK-resistant target cells in MNC from all the patients studied. This in vitro induction of cytotoxic activity in MNC from some patients with glioblastoma by IFN-alpha suggests a potential immunotherapeutic use of the lymphokine in these subjects.

Neuroectodermal tumors of the peripheral and the central nervous system share neuroendocrine N-CAM-related antigens with small cell lung carcinomas.

The current study describes the presence of neuroendocrine antigens of peripheral and central neural tumors using eight monoclonal antibodies raised to small cell lung carcinoma (SCLC), which recognize "neural/neuroendocrine" or "neural" antigens, as defined by their reaction pattern in normal tissues and tumors. At least five of them recognize different epitopes of the neural cell adhesion molecule (N-CAM). It was found that all of 12 neuroblastomas, 2 ganglioneuroblastomas and 4 ganglioneuromas as well as 23 central primitive neuroectodermal tumors, 13 astrocytomas and 4 ependymomas share "neural/neuroendocrine" antigens (as defined by the anti-N-CAM antibodies Moc-1, -21, -32, -52 and -191) with SCLC. The "neural/neuroendocrine" antigen defined by Moc-171 was also found in all peripheral tumors, but only in further differentiated central tumors. Non-N-CAM related "neural" antigens (as defined by Moc-51 and -172) were found only in better-differentiated peripheral and central tumors, but they could be demonstrated in all three medulloblastoma cell lines studied. In addition, the antigen defined by Moc-51 was demonstrated in an immunoblot of a neuroblastoma cell line. Antibodies recognizing "epithelial" antigens of SCLC and other epithelia and their tumors (Moc-31 and -181) were non-reactive. It was concluded that these findings give further support for a relation between neural and neuroendocrine tumors and that some of the antibodies may be useful for the detection of differentiation in neural tumors. Antibodies with an "epithelial" recognition pattern may serve to distinguish neural from neuroendocrine tumors.

The relationship of class I MHC antigen expression to stage IV-S disease and survival in neuroblastoma.

Cultured human neuroblastoma cells express low levels of class I (MHC) surface antigen. In order to determine if this low expression is representative of the clinical tumor, this study investigates class I expression in archival human neuroblastoma. Whereas stages I to IV neuroblastoma expressed low levels of class I antigen, stage IV-S tumor cells expressed normal levels, similar to control tissues. Expression of class I antigen in tumors from survivors of stage III neuroblastoma was significantly greater than in tumors from nonsurvivors. Tumors comprised predominantly of ganglion cells expressed significantly more class I antigen than neuroblasts. These data suggest that class I MHC expression may play a role in the natural history of human neuroblastoma.

[The immunological cellular phenotype and the prognosis in neuroblastoma in children]. / Immunologicheskii fenotip kletok i prognoz pri neiroblastome u detei.

Ganglioside profile was evaluated in 19 samples of tumor tissue obtained from 13 surgical patients with various morphological patterns of neuroblastoma. In six of those cases, two samples from each proving most different in terms of cell maturity were selected for examination. The relative content of GD2 gangliosides was 27.0-37.6% in sympathoblastoma and as low as 5.1-14.8% in ganglioneuroblastoma. Ganglioneuroblastomas showed fairly high levels of GM1 and GD1a gangliosides which were almost completely absent in sympathoblastomas. Ganglioside profile variations seen within each tumor type were incomparable with differences in profile established between morphological patterns of neuroblastoma studied.

Neuropeptide Y- and somatostatin-like immunoreactivities in ganglioneuroma, ganglioneuroblastoma and neuroblastoma.

Neuropeptide Y (NPY)- and somatostatin (SS)-like immunoreactivities (LI) were investigated in tumor tissues of one ganglioneuroma (GN), 3 ganglioneuroblastomas (GNB) and one neuroblastoma (NB) by radioimmunoassay. NPY-LI was detected from all 5 tumor tissues (16.4-1247 pmol/g wet tissue). Sephadex G-50 column chromatography and reverse phase high performance liquid chromatography (HPLC) revealed that most of the NPY-LI in tumor extracts was eluted in an identical position to synthetic human NPY except one GNB (case 2). In this case, most of the NPY-LI was eluted in a higher molecular weight region than synthetic human NPY in Sephadex G-50 column chromatography and in a more hydrophobic position in HPLC. SS-LI was detected from 4 tumor extracts except one GNB (case 2) (21.3-787 pmol/g wet tissue). Sephadex G-25 column chromatography and reverse phase HPLC revealed that SS-LI in tumor extracts was eluted just after the void volume and then in the same positions as SS-28 and SS-14. These results suggest that NPY, SS-14 and SS-28 exist in tumor tissues of GN, GNB and NB, and most of the NPY-LI in one GNB was a higher molecular and more hydrophobic form of NPY-LI.

Expression of neurofilament proteins in the hypertrophic granule cells of Lhermitte-Duclos disease: an explanation for the mass effect and the myelination of parallel fibers in the disease state.

The expression of neurofilament (NF) proteins was examined in the surgical specimen from a 42-year-old woman with Lhermitte-Duclos disease. Hypertrophic granule cell neurons of the dysplastic tissues were reactive with monoclonal antibodies, including antibodies to each of the three human NF subunits. Furthermore, antibodies to dephosphorylation-dependent epitopes on NF proteins stained the cell bodies of hypertrophic granule cells, whereas antibodies to phosphorylation-dependent epitopes stained the enlarged and myelinated axons of the hypertrophic granule cells. Enzymatic dephosphorylation of this tissue abolished axonal staining with phosphorylation-dependent antibodies and uncovered determinants recognized by antibodies to the dephosphorylated state of NF proteins. The NF protein immunoreactivity of hypertrophic granule cells was indistinguishable from that of large, NF-rich neurons in control human cerebellum, suggesting that a normal pattern of expression and phosphorylation of NF proteins occurs in hypertrophic granule cells in Lhermitte-Duclos disease. An increased expression of NF proteins by cerebellar granule cells may account for many of the observed alterations of Lhermitte-Duclos disease, including the hypertrophy of the granule cells and enlargement of their axons, leading to the myelination of parallel fibers within the molecular layer of the cerebellum. Attention should now be directed at the underlying mechanisms which lead to the coordinated up-regulation of the three NF genes and whether or not additional gene products or cell types are altered in Lhermitte-Duclos disease.

Ganglioneuromatous tumor of the skin: a combined heterotopia of ganglion cells and hamartomatous neuroma: report of a case.

We report the histologic and ultrastructural findings of a solitary, unusual cutaneous tumor in a 69-year-old woman. The tumor is characterized by many mature ganglion cells in the papillary dermis and fascicles of unmyelinated axons in the lower dermis. The lesion is ganglioneuromatous but differs from the other ganglioneuromas histologically in that the ganglion cells do not intermingle with the neuromatous elements. It may represent a combined heterotopia of ganglion cells and hamartomatous neuroma. The histologic differential diagnosis and the possible pathogenesis are discussed.

The distribution of immunoreactive chromogranins, S-100 protein, and vasoactive intestinal peptide in compound tumors of the adrenal medulla.

Three adrenal medullary tumors that showed admixtures of pheochromocytomatous elements with ganglioneuroma or ganglioneuroblastoma were studied to determine the distribution of immunoreactive chromogranins, S-100 protein, and vasoactive intestinal peptide (VIP). Two tumors consisted of typical pheochromocytoma cells admixed with mature-appearing ganglioneuroma. The third consisted of pheochromocytoma admixed with ganglioneuroblastoma and contained many immature and cytologically atypical cells. In all cases, chromogranin staining was absent or weak in neuronal perikarya and moderate to intense in varicosities of neuronal processes, a finding consistent with the presumed distribution of secretory granules in neurons. Chromogranin staining was also intense in chromaffin cells. Glial cells that stained for S-100 were randomly scattered among chromaffin cells but accumulated in areas with neuronal processes. Weak staining for VIP was present in neuronal cells in one of the two tumors with ganglioneuromatous features. Intense staining for VIP occurred in the third tumor in both neuronal and apparently nonneuronal cells. We conclude that granule distribution and cell-cell interactions for specific cell types in compound tumors tend to mimic those in normal adrenal medulla and sympathetic ganglia. Although immunoreactive VIP was localized exclusively to neurons in one tumor, as in normal tissues, patterns of staining for VIP across tumors are less predictable.

Establishment and characterization of human neuroblastoma and ganglioneuroblastoma cell lines.

The establishment in culture and characterization of 4 human neuroblastoma (NB) cell lines and 1 human ganglioneuroblastoma cell line are described. Each cell line fulfilled at least 2 of 4 criteria for malignant or transformed cells: viz., subcultured more than 70 times, high saturation density with absence of contact inhibition, population-doubling time within a range of 10-40 h, and tumour formation in nu/nu mice. Each cell line also fulfilled at least 2 of 3 criteria for neuroblastoma cells: viz., humoral and cell-mediated immune reactivity toward NB-associated cell-surface antigen, intracellular storage and extra-cellular secretion of catecholamines, and characteristic neuroblast and ganglion-cell morphology.

Primary pulmonary ganglioneuroblastoma in an adult: maturation, involution and the immune response.

The features of a primary pulmonary ganglioneuroblastoma occurring in an adult are presented. The tumour showed evidence of both maturation and involution. Maturation appeared to be occurring in a centrifugal manner, a rim of mature ganglioneuromatous tissue enclosing the primitive neuroblastoma. Necrosis of the neuroblastomatous element was widespread and associated with deposition in the walls of numerous small vessels of an amorphous eosinophilic amyloid-like material. Accumulation of this material had led to occlusion of some vessels with resultant necrosis of related tumour. A collarette of lymphocytes surrounded the tumour, and lymphocytic aggregates were prominent at the interface between neuroblastoma and ganglioneuroma. Despite widespread vascular invasion, the patient remains well and apparently tumour-free, 2 1/2 years post-resection. The appearances may represent a combined cellular and humoral host response, and a possible relationship of this response to tumour maturation is suggested. The potential role of immunostimulation in the treatment of neuroblastoma is discussed.