Frequent expression of somatostatin receptor 2a in olfactory neuroblastomas: a new and distinctive feature.

Olfactory neuroblastoma (ONB) is a malignant neuroendocrine neoplasm with a usually slow course, but with considerable recurrence rate. Many neuroendocrine tumors have shown good response to the treatment with somatostatin analogs and somatostatin radioreceptor therapy. In ONBs, there are scarce data on somatostatin-based treatment and the cellular expression of somatostatin receptors (SSTR), the prerequisite for binding and effect of somatostatin on normal and tumor cells. The aim of our study was to investigate the immunohistochemical expression of SSTR2A and SSTR5 in a cohort of 40 ONBs. In addition, tissue microarrays containing 40 high-grade sinonasal carcinomas as well as 6 sinonasal lymphomas, 3 rhabdomyosarcomas, and 3 Ewing sarcomas were evaluated. Volante system was applied for staining evaluation. Thirty cases (75%) were immunopositive for SSTR2A and 3 (7.5%) for SSTR5. Among the 30 SSTR2A-positive ONBs, 19 tumors (63.3%) scored 2+ and 11 (36.7%) scored 3+. All SSTR5-positive ONBs scored 2+. Neither sinonasal carcinomas nor sinonasal small round blue cell neoplasms expressed SSTR2A or SSTR5. The frequent expression of SSTR2A provides a rationale for radioreceptor diagnosis and therapy with SST analogs in ONBs. SSTR2A expression in ONBs is a helpful adjunct in the differential diagnosis of ONBs.

Metastatic esthesioneuroblastoma in a horse.

A 17-year-old horse developed severe proptosis of the left eye over a period of 1.5 years. At post-mortem examination a neoplasm was found involving the left ethmoid bone, left maxillary sinus, left orbit, left superior turbinate, and the left eye. Tumour cells were arranged in nests separated by a fine fibrovascular stroma. Immunohistochemically, the tumour cells were labelled by antibodies against neurofilament protein, synaptophysin, glial fibrillary acidic protein and S-100 protein antigen, but were negative for chromogranin A, cytokeratin and desmin. Electronmicroscopically, the cells showed neurosecretory granules with an electron-dense centre and a light halo, and microfilaments. On the basis of macroscopical, light microscopical and ultrastructural findings a diagnosis of a metastatic esthesioneuroblastoma was made.

Is esthesioneuroblastoma a peripheral neuroectodermal tumor?

Esthesioneuroblastoma (ENB; olfactory neuroblastoma) is a rare, locally aggressive neoplasm of the sinonasal area and anterior cranial fossa. The histogenesis of the lesion is not clearly delineated, and the broad histological spectrum of ENB has confounded the issue. The location, histological features (neuropil, Homer Wright, and olfactory rosettes), and reported immunocytochemical reactions (neuron-specific enolase (NSE) and chromogranin (CHR) positivity) suggest that ENB may be a neural or neuroendocrine neoplasm derived from the olfactory membrane. Recent demonstration in two of three metastatic putative ENB cell lines of the 11;22 chromosomal translocation, seen in Ewing's sarcoma (ES) of bone and peripheral neuroectodermal tumors (PNET) of bone and soft tissue, has led to the conclusion that ENB may be closely related histogenetically to PNET. The overwhelming majority of cases of ES and PNET express the protein product of MIC-2, a gene located on the pseudoautosomal region of the X and Y chromosomes. This protein can be identified immunocytochemically by antibodies 12E7, HBA71, and ON13. We studied the expression of MIC-2 using the 12E7 antibody as well as multiple neural markers in 18 ENB samples obtained from the files of The Johns Hopkins Hospital. The patients ranged in age from 19 to 90 years (mean, 47.5; median, 47) and included five men and 13 women. None of the 18 specimens reacted with antibody 12E7, but 16 were positive for NSE, nine reacted to synaptophysin (SYN), and 13 showed antibodies to chromogranin (CHR). Our studies agree with the previous suggestions that ENB is a primitive neural tumor but fail to support the hypothesis that it is a member of the PNET family.

Ectopic Cushing's syndrome caused by an esthesioneuroblastoma.

OBJECTIVE: To report a case of florid Cushing's hormone (ACTH) secretion related to the presence of an esthesioneuroblastoma (ENB). METHODS: We present clinical, laboratory, and pathologic findings in a 36-year-old Caucasian man presenting with Cushing's syndrome. Results of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and somatostatin receptor scintigraphy are presented, along with tumor pathology findings. RESULTS: After initial biochemical studies suggestive of ectopic Cushing's syndrome, CT of the chest and abdomen revealed multiple cavitated pulmonary lesions, an ischiorectal mass, and bilateral adrenal hyperplasia. MRI of the pituitary gland revealed normal findings. Both PET scanning with [18 F]-flurodeoxyglucose (FDG) and somatostatin receptor scintigraphy with 111 indium-penetetreotide (Octreoscan) revealed strong tracer uptake in the ethmoid region. CT and MRI of the sinuses and brain subsequently localized a 5-cm mass in the ethmoid sinuses with intracranial extension. On biopsy, pathology results were consistent with a diagnosis of ENB, and immunohistochemical analysis revealed that tumor cells were strongly positive for ACTH, synaptophysin, and S-100, providing definitive diagnosis of ACTH-producing ENB. Hypercortisolemia was initially controlled by metyrapone, then by external beam radiation therapy (RT). CONCLUSION: This case illustrates the usefulness of nuclear imaging in the diagnosis of ENB, and the importance of prompt control of hypercortisolemia in Cushing's syndrome.

Fine needle aspiration cytology of metastatic olfactory neuroblastoma.

OBJECTIVE: Olfactory neuroblastoma (ONB) is an uncommon malignant neoplasm that originates in the upper nasal cavity. Cytomorphologic descriptions of ONB have been limited to isolated case reports. The features of a series of metastatic ONB diagnosed by fine needle aspiration (FNA) are described. STUDY DESIGN: Cytologic findings in four patients with ONB metastatic to cervical lymph nodes who underwent FNA were reviewed, and the cytomorphologic findings were summarized. Immunocytochemical findings and ultrastructural features with selected immunoelectron microscopy from three cases are described. RESULTS: Aspiration cytology revealed a predominance of single cells with intermixed small, loosely cohesive, three-dimensional cell groups. Cell size was small to intermediate, with round nuclei. There was an overall monomorphic appearance, with minimal nuclear pleomorphism. Chromatin was finely granular and stippled, with multiple, small chromocenters. Cytoplasm in the cell groups had a fibrillary quality and was moderate in amount. Single nuclei were frequently stripped of cytoplasm. Occasional pseudorosettes were noted. Immunocytochemical stains were positive for both neuronspecific enolase and synaptophysin. Ultrastructural examination showed neuritic cell processes with neurosecretory granules and microtubules. Immunoelectron microscopy showed positive labeling of neurosecretory granules by chromogranin A. CONCLUSION: FNA cytomorphology, in combination with ancillary studies, can provide an accurate diagnosis of metastatic ONB.

[Olfactory esthesioneuroma (esthesioneuroblastoma). A pathologic study of 7 cases]. / Les esthésioneuromes (esthésioneuroblastomes) olfactifs. Etude anatomopathologique à propos de 7 observations.

With an histological, immunohistochemical study of 7 cases of olfactory esthesioneuromas (4 of them had an ultrastructural study), our purpose was to revise the problem of the too often ambiguous terminology and of the different histological lower classes classifications of these tumors. Our own results and the literature demonstrate that they are polymorphic. In standard histology, they are often right diagnosed but an immunohistochemical study can be useful and an ultrastructural study absolutely necessary for a reliable diagnosis. For an easier nomenclature, we advise to use only one terminology for these tumors = olfactory esthesioneuroma. But, because of their important polymorphism, we keep to an histological lower classes classification according to their degree of differentiation in light microscopy: well differentiated tumors (old esthesioneuroepitheliomas), moderately differentiated tumors (old esthesioneurocytomas), poorly differentiated tumors (old esthesioneuroblastomas and so on described as neuro-endocrine carcinomas by Silva and al).

[Olfactory neuroblastoma: a histopathological ultrastructural and immunohistochemical study of 11 cases].

Eleven cases of olfactory neuroblastoma (ONB) were studied histopathologically, ultrastructurally and immunohistochemically. Light microscopical examination showed the tumor cell nests separated by fibrous connective tissue (present in 10/11 ONB), Homer-Wright rosette and/or Flexner rosette (9/11 ONB) and acidophilic fibrillary background (8/11 ONB). Ultrastructurally, there were neurosecretory granules (2/2 ONB) and neurofibrils (1/2 ONB) in cytoplasm of tumor cells. A panel of antibodies were used to characterize the immunohistochemical staining profile of ONB. The following results were obtained for the 11 neoplasms that were immunostained: NSE 11/11 (+), S-100 3/11 (+), Vimentin 4/11 (+), Keratin 1/11 (+) and NF, EMA, CEA, LCA all negative respectively. The significance of the morphological and immunohistochemical features of ONB in diagnosis and differential diagnosis were discussed.

[Olfactory esthesioneuroblastoma: scintigraphic expression of somatostatin receptors]. / Estesioneuroblastoma olfatorio: expresión gammagráfica de receptores de somatostatina.

Esthesioneuroblastoma is an uncommon tumor originating in the upper nasal cavity and constitutes 3% of all intranasal neoplasms. Few references exist about the expression of somatostatin receptors in these tumors. Our case demonstrates a good correlation between the somatostatin receptor scintigraphy and magnetic resonance imaging.

Olfactory neuroblastoma with focal ganglioneuroblastic differentiation: a case report with literature review.

Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumour, with clearly defined histologic and immunohistochemical features, that typically arises in the superior nasal cavity. Although the classical clinicopathological features leave little room for misinterpretation, the wide variability in this tumour, including occasional divergent differentiation, may cause diagnostic difficulty. Herein, an unusual case of ONB with focal ganglioneuroblastic differentiation in an 81-year-old woman arising from the anterior ethmoid, filling the upper portion of the left nasal cavity and sparing the sinus cavities, is described. Histologically, the tumour was composed of atypical monotonous round cells that were positive for NSE, CD56, chromogranin, synaptophysin, neurofilament and calretinin and exhibited an irregular lobulated and nested growth pattern and sparse mitotic figures (3 to 4 mitoses per 10 HPF). Focally, the histology changed to ganglioneuroblastic differentiation consisting of large ganglion and spindle cells, positively staining for S-100, GFAP, CD99, neurofilament, calretinin, chromogranin and synaptophysin. Neuroblastomas, occurring in the nasal cavity, in analogy to other sites, tend to have an aggressive biologic behaviour and can histologically mimic other undifferentiated malignant neoplasms of the sinonasal tract. Differential diagnostic problems are discussed; a comprehensive review of the literature has also been performed with a focus on survival.

Primary sellar neuroblastoma. A new case and review of literature.

The primary intracranial development of olfactory neuroblastomas, outside olfactory epithelium, is rare. We report a case of primary sellar neuroblastoma without any aggressive histopathological features, managed solely surgically without adjuvant therapy, with good outcomes at 3 years. Primary sellar neuroblastomas mostly occur in women in the 4th decade with a context of a non-secreting pituitary tumour. Diagnosis is made on histopathological examination (small cells, fibrillary intercellular background, strong immunoreactivity for neurons markers, negative immunoreactivity for anterior pituitary hormones). Management is based on surgery. Adjuvant treatment is not consensual, largely depends on patient's conditions and aggressive histopathological features.

Olfactory neuroblastoma causing ectopic ACTH syndrome.

A 39-year-old woman who presented with typical Cushingoid appearance (moon facies, central obesity, purpura) was admitted to our hospital because of pulmonary infection. She was found to have hypertension, severe hypokalemia, and metabolic alkalosis. Endocrine data revealed elevated plasma levels of ACTH and cortisol with lack of circadian rhythm, non-suppressibility to high-dose dexamethasone, and hyperresponsiveness to CRH stimulation. Although no pituitary mass was detected by MRI of the brain, inferior petrosal sinus sampling showed a step-up of central to peripheral ACTH levels; these data are consistent with the diagnosis of Cushing's disease. She was successfully treated with metyrapone to control hypercortisolemia. Ten months later, a mass was detected in the ethmoid sinus, which was surgically removed. After resection of the ethmoid sinus tumor, her Cushingoid features and hypercortisolemia disappeared, but recurred after enlargement of a second mass in the maxillary sinus. After resection of the maxillary sinus tumor, her hypercortisolemia subsided. Histologically, the tumor tissues from both the ethmoid and maxillary sinus were identical and consistent with the diagnosis of olfactory neuroblastoma. Immunohistochemically, the immunoreactivities of ACTH and POMC were positive in the cytoplasm of tumor cells, and immunoreactive ACTH was demonstrated in both tumor tissues. Thus, this is the second rare case with ectopic ACTH syndrome caused by olfactory neuroblastoma thus far reported.

An ultrastructural and immunohistochemical study of olfactory neuroepithelioma with rhabdomyoblasts.

A rare case of olfactory neuroepithelioma with rhabdomyoblasts in a 61-year-old man was investigated using electron microscopic and immunohistochemical methods. A large tumor enhanced by gadolinium-diethylenetriamine pentaacetic acid (DTPA) was demonstrated on magnetic resonance imaging (MRI), located within the anterior cranial fossa without bone destruction. The tumor mostly consisted of small cells with scant cytoplasm. Tubular rosettes were often found. Immunoreactivity for cytokeratin and epithelial membrane antigen (EMA) was strongly positive. Most of the tumor cells were shown to be positive for neuron-specific enolase (NSE) and vimentin and weakly positive for synaptophysin and S-100. Rhabdomyoblasts, which showed oval cells with abundant eosinophilic cytoplasm and a nucleus sometimes displaced toward the periphery of the cell body, were frequently intermingled with the tumor cells. The immunoreactivity for myoglobin was frequently positive in these oval cells. The MIB-1 index showed high values, of 20%-40%. About 10% of the tumor cells revealed positivity for p53 protein and vascular endothelial growth factor (VEGF). Ultra-structurally, numerous junctional complexes were observed between cell bodies and processes. The cell processes frequently contained numerous microtubules. There were sometimes numerous filaments with small aggregates of Z-band material and thick filament-ribosomal complexes in the oval cells. They were concluded to be consistent with rhabdomyoblasts on light microscopic and immunohistochemical findings.

[Co-expression of TrkA and p75 neurotrophin receptor in extracranial olfactory neuroblastoma cells].

OBJECTIVE: To determine whether TrkA and p75 are expressed in olfactory neuroblastoma (ON) and whether the evaluation of their expression by immunohistochemistry is useful to predict the outcome of ON. METHODS: Ten cases of ON and 5 nasopharyngeal carcinoma and 5 normal olfactory neuroepithelial of nasal cavity were examined for the expression of TrkA and p75 neurotrophin receptors using immunohistochemistry and double fluorescence labeling. RESULTS: The 10 cases of ON showed positive immunohistochemical staining for both TrkA and p75. Double staining revealed that almost all TrkA immunoreactive ON cells also contained p75 immunoreactive. In contrast, no TrkA or p75 immunoreactivity was detected in nasopharyngeal cells and normal olfactory neuroepithelial cells. CONCLUSION: Nerve growth factor may play a role in the generation of ON and staining of TrkA and p75 may assist diagnosis of ON.

Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing's group.

Esthesioneuroblastoma (ENB) is a rare, site-specific, locally aggressive neuronal malignancy so far thought to belong to primitive peripheral neuroectodermal tumour-Ewing's tumour (pPNETs-ETs). Its anatomical location, in addition to morphologic, immunophenotypic and ultrastructural features, suggests its origin in the neuronal or neuroendocrine cells of the olfactory epithelium. However, the cytogenetic and molecular data currently available appear controversial on the presence of the typical translocation t(11;22)(q24;q12) and of trisomy 8, chromosomal changes that characterize the tumours belonging to the pPNETs-ETs. Herein we have analysed five ENB tumour specimens for trisomy 8 by fluorescence in situ hybridization (FISH), for the presence of EWS gene rearrangements by FISH, reverse transcription polymerase chain reaction and Southern blot analyses, as well as for the expression of the Ewing sarcoma-associated MIC2 antigen by immunohistochemistry. Neither EWS/FLI-I, EWS/ERG and EWS/FEV fusion genes nor MIC2 expression were found in any tumour, whereas trisomy 8 was found in one case only. Moreover, DNA from three cases analysed by Southern blot did not show EWS gene rearrangements. Our results support the evidence that ENB is not a member of the pPNETs-ETs.

[Olfactory neuroblastoma. Presentation of a case]. / Il neuroblastoma olfattorio. Presentazione di un caso.

Olfactory neuroblastoma is an uncommon and hardly diagnosable neoplasm. The conventional histologic analysis allows generally a diagnosis of undifferentiated carcinoma. The immunohistochemical procedures, particularly the S-100 Protein and the Enolase Neuron-Specific, may contribute to define the diagnosis as well as in a patient recently observed by the authors.

Olfactory neuroblastoma and other round cell lesions of the sinonasal region.

Sixty-nine round cell lesions of the sinonasal region (22 olfactory neuroblastomas [ONBs], 17 malignant lymphomas, nine Ewing's sarcomas [ES], nine rhabdomyosarcomas, three sinonasal undifferentiated carcinomas, five malignant melanomas, and four pituitary adenomas) were studied in an attempt to define the differential diagnostic capabilities of antibody to MIC2 and bcl-2 in paraffin-embedded tissue in the distinction of these lesions. In addition, antibody to p53 was applied in each case to define the incidence of p53 positivity among these various tumor types. Each of the ES cases was MIC2 positive; each of the other cases was MIC2 negative. Positivity for bcl-2 was confined to two cases, one of them a malignant lymphoma (85% of cells positive) and one an ONB (5% of cells positive). Small numbers of scattered p53-positive cells appeared in the majority of cases studied, without regard for the specific tumor type; only a single case, a malignant lymphoma, showed a majority (approximately 90%) of p53-positive cells. These results indicate that the MIC2 antibody is a useful method by which to distinguish ES from a variety of other round cell lesions that may be encountered in the sinonasal region. The practical applications of antibody to bcl-2 and p53 seem to be much more limited; by contrast, neither bcl-2 positive cells nor abundant p53 cells identified by immunohistochemical analysis seemed to be frequent findings in any of the tumor types studied. Although ONBs have been included with the peripheral primitive neuroectodermal tumors for classification purposes, these tumors diverge from the ES/primitive neuroectodermal tumor family in that they do not seem to share either the MIC2 positivity or the t(11;22) chromosomal translocation that typify the ES/primitive neuroectodermal tumor family of lesions. Although bcl-2 positivity has been associated with a light microscopic finding of an unfavorable histologic pattern in retroperitoneal neuroblastomas, it does not seem that bcl-2 positivity in ONB will select for a clinically distinctive subset of patients.