TROY (TNFRSF19) is overexpressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling

A critical problem in the treatment of malignant gliomas is the extensive infiltration of individual tumor cells into adjacent brain tissues. This invasive phenotype severely limits all current therapies, and to date, no treatment is available to control the spread of this disease. Members of the tumor necrosis factor (TNF) ligand superfamily and their cognate receptors regulate various cellular responses including proliferation, migration, differentiation, and apoptosis. Specifically, the TNFRSF19/TROY gene encodes a type I cell surface receptor that is expressed on migrating or proliferating progenitor cells of the hippocampus, thalamus, and cerebral cortex. Here, we show that levels of TROY mRNA expression directly correlate with increasing glial tumor grade. Among malignant gliomas, TROY expression correlates inversely with overall patient survival. In addition, we show that TROY overexpression in glioma cells activates Rac1 signaling in a Pyk2-dependent manner to drive glioma cell invasion and migration. Pyk2 coimmunoprecipitates with the TROY receptor, and depletion of Pyk2 expression by short hairpin RNA interference oligonucleotides inhibits TROY-induced Rac1 activation and subsequent cellular migration. These findings position aberrant expression and/or signaling by TROY as a contributor, and possibly as a driver, of the malignant dispersion of glioma cells.     

Fine needle aspiration cytology of malignant spiradenoma arising in congenital eccrine spiradenoma

The fine needle aspiration (FNA) cytology of malignant eccrine spiradenoma arising in a large benign congenital eccrine spiradenoma is described. The malignant tumor was characterized by cohesive, pleomorphic cells with malignant nuclear features and numerous mitoses. FNA of the adjacent benign eccrine spiradenoma revealed prominent basement membrane deposition with an irregular tubular and nesting growth pattern and bland basaloid cells. To our knowledge, the FNA of malignant eccrine spiradenoma has not been previously described. In this case, FNA cytology was influential in directing patient management.     

Changes in the level of glial fibrillary acidic protein (GFAP) after mild and severe focal cerebral ischemia

In the present study, we examined the temporal and spatial expression profiles of GFAP mRNA and protein in a focal cerebral ischemia model with ischemic injury confined to the cerebral cortex in the right middle cerebral artery (MCA) territory. Northern blot analysis showed a respective 5.5-fold and 7.2-fold increase in the GFAP mRNA in the ischemic right MCA cortex in rats subjected to 30-min (mild) or 60-min (severe) ischemia followed by 72-hr reperfusion. The GFAP mRNA signal remained elevated up to 2-week reperfusion. Interestingly, increased GFAP mRNA signal was clearly demonstrated for the first time in the left MCA cortex. A significant 1.5-fold and 5-fold increase was observed after 72-hr reperfusion following mild and severe ischemia, respectively. However, unlike the ischemic right MCA cortex, this induction was transient in the non-ischemic left MCA counterpart. In situ hybridization studies further revealed characteristic spatial induction profile following mild vs. severe ischemia. In mild ischemia, following 24-hr reperfusion, increase in GFAP mRNA was observed mainly within the ischemic right MCA cortex. Following 72-hr reperfusion, GFAP mRNA signal was observed in virtually the entire ischemic cortex, particularly the amygdala region, then gradually reduced and restricted to right MCA territory and subcortical thalamic nucleus following 2-week reperfusion. On the other hand, in severe ischemia, following 24-hr reperfusion increased GFAP mRNA signal was observed in area surrounding right MCA territory (infarct region) and outer cortical layers within the right MCA territory. Following 72-hr reperfusion, no signal was detected within right MCA cortex; however, increased GFAP signal was detected throughout the remaining ipsilateral cortex and subcortical region, as well as the contralateral cerebral cortex. GFAP mRNA signals then gradually reduced its intensity and was restricted to area surrounding necrosis and ipsilateral thalamic nucleus following 2-week reperfusion. GFAP-like immunoreactivity was also detected in area expressing GFAP mRNA. It is very likely that de novo synthesis was responsible for this increase. In summary, increased GFAP signal was noted in both ipsilateral and contralateral cerebral following mild and severe ischemia. Although the temporal induction profile for mild vs. severe ischemia was similar, the spatial induction profile was different. The mechanism leading to this differential induction and their physiological and functional significance are not clear at present. It is very likely that some local factors may involve, nevertheless, the detailed mechanisms remain to be fully explored.     

R3: Invasive salivary duct carcinoma ex pleomorphic adenoma of the parotid gland: a teaching case giving rise to the genuine diagnostic difficulty on an inadequate cytology specimen

ABSTRACT: A history of a recent rapid increase in long-standing swelling mass was presented in the right parotid gland of an 85-year-old male. The inadequate cytologic specimens contained few small clusters of three-dimensional malignant epithelial cells having hyperchromatic pleomorphic nuclei and prominent nucleoli, adjacent to a cluster of benign monomorphic myoepithelial cells. We first interpreted it merely as an adenocarcinoma, not otherwise specified. A radical parotidectomy was performed, and gross examination revealed an encapsulated and firm tumor lesion, looking grayish-blue to yellowish-white, focally associated with extracapsular invasion. On microscopic examination, the tumor was predominantly composed of a proliferation of highly atypical epithelial cells having abundant eosinophilic cytoplasm, often arranged in a Roman-bridge appearance with foci of comedo necrosis, alternating with extensive infiltration to adjacent stroma in a trabecular or alveolar fashion with severe vessel permeation. Within the background of pleomorphic adenoma, the carcinoma cells sometimes replaced ductal luminal cells while retaining an intact-like myoepithelial layer. Therefore, we finally made a diagnosis of invasive salivary duct carcinoma ex pleomorphic adenoma. We should be aware that owing to its characteristic features, cytopathologists might be able to determine correct diagnosis, based on multiple and adequate samplings. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2126158270695815.     

Primary squamous cell carcinoma of the thyroid diagnosed by fine needle aspiration cytology. A report of two cases.

BACKGROUND: Primary squamous cell carcinoma of the thyroid is a rare malignant tumor that needs to be distinguished from other neoplasms. CASES: Two males aged 65 and 68 years presented with an enlarged right lobe of the thyroid. Thyroid scintigraphy revealed a cold nodule. Clinically malignancy was suspected. Fine needle aspiration (FNA) revealed numerous clusters and isolated malignant cells, dyskeratotic cells and deposits of eosinophilic granular keratin material. Subtotal thyroidectomy was performed. Histologic findings confirmed the cytologic diagnosis of squamous cell carcinoma. CONCLUSION: Primary squamous cell carcinoma of the thyroid is a rare tumor. FNA findings of this tumor were not reported before. FNA study cannot help to differentiate primary from metastatic squamous cell carcinoma of the thyroid.     

Cytomorphologic diagnosis of malignant lymphoma arising in the heart: a case report.

BACKGROUND: Primary malignant lymphoma of the heart is extremely rare. Because its clinical signs and symptoms are typically nonspecific, it is often very difficult to detect cardiac involvement while the patient is alive. We describe a case of malignant lymphoma involving predominantly the heart and pericardium and diagnosed by pericardiac effusion cytology antemortem. CASE: An 83-year-old woman presented with dyspnea on exertion. Echocardiography revealed a low-echoic tumor mass close to the right ventricular wall and massive pericardiac effusion. Diagnosis of diffuse large B-cell lymphoma was made by cytomorphologic examination and flow cytometry of the tumor cells obtained from the effusion. Although chemotherapy was instituted immediately, the patient died of progressive heart failure. Diffuse large B-cell lymphoma predominantly involving the intracardiovascular region was confirmed at autopsy. CONCLUSION: From the experience in this case, we conclude that cytopathologic examination of sonographically guided aspiration of the cardiovascular region is very useful for antemortem diagnosis of primary malignant lymphoma of the heart.     

Double primary lung cancers: with special reference to their exfoliative cytology and to the rare, malignant "mixed" tumor of the salivary-gland type

Two autopsy cases are reported in which double primary cancers of the lung had been strongly or definitely suspected before death by demonstration of two different types of malignant cells in the sputum as well as in smears of aspirates from pleural fluid and/or mediastinal tumor. By exfoliative cytology, one case was characterized by carcinoma cells of the small-cell type plus the large-cell and/or adenocarcinoma type; the other displayed small-cell-type and squamous-cell-type malignant cells. The autopsies definitely revealed in the first case an anaplastic carcinoma of the small-cell type in the left bronchus and a salivary-gland-type malignant "mixed" tumor in the right lower lobe and in the second case an anaplastic carcinoma of the small-cell type in the right upper lobe and a squamous-cell carcinoma in the left upper lobe. The frequence of occurrence and pathologic diagnosis of double primary lung cancers are reviewed and discussed. A rare type of lung cancer, salivary-gland-type malignant "mixed" tumor, is given special reference.     

A late recurring and easily forgotten tumor: ovarian granulosa cell tumor

ABSTRACT: Ovarian granulosa cell tumor (GCT) is a malignant tumor with slow progression. The recurrence of granulosa cell tumor often happens after 5 years, leading to a 'forgotten tumor' by the patient. We present the case of a 64-year-old woman with a presentation of left flank pain. An initial computed tomography scan revealed a single tumor with multiple adjacent organ invasions. Surgical intervention was prescribed and the pathological results revealed a metastatic granulosa cell tumor. We also review the literature for the follow-up and further management of this tumor.     

Down-regulation of brain muscarinic cholinergic receptor promoted by diacylglycerols and phorbol ester

Sustained agonist stimulation induces an asymmetric down-regulation of brain muscarinic acetylcholine receptor (mAChR): 43±2% in the right and 26±2% in the left cerebral hemisphere, respectively (Ref. 1). In order to determine the possible involvement of endogenous diacylglycerols produced under muscarinic stimulation in the down-regulation phenomenon, here we have studied the effects of synthetic diacylglycerols and a phorbol ester on cells dissociated from rat cerebral cortex. Oleoylacetylglycerol decreased the amount of cell-surface mAChR by 37±2% and 25±2% in right and left cerebral cortex, respectively. Long-term treatment with phorbol dibutyrate also produced internalization of the mAChR (25±1.5% and 33±2% in right and left cortical cells, respectively). These changes occurred without modification of the Kd_app for the selective antagonist pirenzepine. The action of calcium ions was also studied using incubation of cells with the ionophore A23187. No changes were observed in the amount of mAChR detected at the plasma membrane with the ionophore alone, but when used in combination with phorbol dibutyrate and the agonist carbamylcholine a sinergistic decrease in mAChR was apparent. It is concluded that long-term exposure to exogenously added diacyglycerols and phorbol ester significantly reduces the amount of mAChR detected at the plasma membrane and abolishes the asymmetry of the down-regulation phenomenon observed under specific muscarinic stimulation, suggesting that diacylglycerols may be one of the factors responsible for such asymmetry.Abbreviations used A23187 ionophore A23187 - ATRO atropine - CARB carbamoylcholine - DAG diacylglycerol - DMEM Dulbecco's modified Eagle's medium - DMSO dimethylsulfoxide - HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) buffer - PZ pirenzepine - LCC left cerebral cortex - mAChR muscarinic acetylcholine receptor - OAG oleoylacetylglycerol - PDB phorbol dibutyrate - RCC right cerebral cortex     

Anatomical brain asymmetry in monkeys: frontal, temporoparietal, and limbic cortex in Macaca

Measurements evaluating possible cerebral hemispheric asymmetries were taken by hand on frontal, parietal, and temporal cortex on 60 formalin-fixed Macaca mulatta and Macaca fascicularis brain specimens. No statistically significant (P less than 0.05) right/left side differences in the mean length of four sulci in visual-processing areas of the cortex were found. The sulcus adjacent to the region cytoarchitecturally homologous to the motor speech area in the human brain did not show pronounced asymmetry. In both species, however, a small parietal lobe sulcus showed greater development on the left hemisphere than in the right. In measurements made using digital planimetry, right/left side differences in the area of the dorsal cingulate gyrus were not found. Behavioral evidence suggests that monkeys do not exhibit a consistent pattern of cerebral dominance for functions associated with most of these regions of the brain.     

Functional Asymmetry of the Brain and Ignoring of the Environment

Manifestations of functional asymmetry of human cerebral cortex at spatial orientation in the visual and auditory systems are considered. Disorder of the right hemisphere activity leads to two main interrelated disorders: ignoring of a portion of the extrapersonal space on the left and compression of this space on the right. The revealed disorders are considered as a result of suppression of activity of brain structures (first of all, of the parietal area of the right cortex) that form body scheme (the reference level at the spatial orientation). The suggestion is made about causes of ignoring of the external sensory space in disturbances of the right parietal cortex area. Role of the right hemisphere in other possible forms of ignoring of the external space is considered.     

An immunohistochemical localization of neuropeptide Y (NPY) in its amidated form in human frontal cortex

The distribution of neuropeptide Y (NPY)-immunoreactive neurons was studied in human frontal cerebral cortex from surgical biopsy specimens by immunohistochemical techniques. NPY-containing neurons were identified in all cortical sublayers except sublayer I. The stained neurons were of the multipolar, bitufted, round or triangular form with dendritic and axonal processes. The immunoreactive neurons were considered to be cortical interneurons, due to their nonpyramidal form, and since their processes could be followed intracortically particularly in direction to superficial cortical layers. The NPY precursor molecule is processed to NPY by a dibasic cleavage, and NPY is further enzymatically amidated before release and receptor activation can be achieved. Antisera raised against Cys-NPY(32-36)amide recognize amidated NPY not cross-reacting with nonamidated NPY. These antisera and immunohistochemistry revealed the presence of a population of NPYamide-immunoreactive cells morphologically indistinguishable from the NPY-immunoreactive cells in the human frontal cortex. By comparing the number of immunoreactive cells in adjacent sections, it appears that the number of NPY-immunoreactive cells was higher than those immunoreactive to NPYamide. Also, the density of NPY fibers was much higher compared with the number stained with NPYamide antiserum. The present immunohistochemical study indicates that NPY in its amidated form is contained in a subpopulation of human cortical NPY-immunoreactive neurons and may participate as an active neurotransmitter/modulator within the human cerebral cortex.     

Fine needle aspiration cytology in recurrent amelanotic melanoma: a case report

BACKGROUND: Amelanotic melanoma can mimic a wide variety of epithelial and nonepithelial malignant tumors. Varied cytomorphology of melanoma has been described on exfoliative and fine needle aspiration cytology (FNAC). We report a case of recurrent amelanotic melanoma to highlight its varied cytomorphologic features, which may cause diagnostic problems on cytologic and on histologic examinations. CASE: A 63-year-old male presented with nodular swellings in the right anterior chest wall, right axilla and back. A nodule in the chest had been excised 6 months earlier. Clinically, the lesion was interpreted as recurrent soft tissue sarcoma. FNAC revealed malignant cells with highly varied morphology with plasmacytoid and pleomorphic malignant cells with occasional fibrocollagenous tissue strands showing adherent neoplastic cells. A cytologic diagnosis of pleomorphic malignant tumor was suggested, and the original histologic slides were reviewed; they showed a striking alveolar pattern that vaguely resembled an alveolar rhabdomyosarcoma. However, on immunohistochemistry, the tumor cells were S-100 and melan-A positive and desmin negative. A final diagnosis of amelanotic melanoma was made. CONCLUSION: Awareness of the highly varied cytomorphology of amelanotic melanoma minimizes the diagnostic difficulty on fine needle aspiration smears. Suitable immunohistochemical markers are of great value in difficult situations.     

Malignant phyllodes tumor of the breast metastatic to the parotid gland diagnosed by fine needle aspiration biopsy. A case report

BACKGROUND: Phyllodes tumor (cystosarcoma phyllodes) is a rare fibroepithelial neoplasm of the breast. Malignant phyllodes tumor is characterized by an infiltrative border and marked degree of hypercellular stromal overgrowth with > 5 mitoses per 10 high-power fields. Distant metastasis occurs in 10-20% of patients with malignant phyllodes tumor. The most common sites of distant metastases are the lungs, bone and abdominal viscera. Although theoretically any organ may have metastasis, the parotid gland has not been documented before in the English-language literature. CASE: A 40-year-old, Caucasian woman with a history of malignant phyllodes tumor of the left breast presented with a mass on the right side of the parotid gland. Fine needle aspiration biopsy of the mass revealed abundant discohesive spindle cells showing moderate nuclear pleomorphism with occasional mitoses. No epithelial elements were seen. A diagnosis of malignant spindle cell tumor consistent with metastatic malignant phyllodes tumor was made. Histology confirmed the cytologic diagnosis. CONCLUSION: Fine needle aspiration biopsy is accurate and efficient in conjunction with clinical information in the diagnosis of malignant phyllodes tumor of the breast metastatic to the parotid gland.     

FNAC in the diagnosis of recurrent dermatofibrosarcoma protuberans of the forehead. A case report

BACKGROUND: Dermatofibrosarcoma protuberans is a rare cutaneous soft tissue tumor of intermediate malignant potential with a characteristic tendency for recurrence. Metastases are unusual. This tumor usually occurs in the trunk and extremities and, infrequently, on the face and scalp. Its cytologic appearance on fine needle aspiration has only been rarely reported. It is characterized by numerous fibroblastlike cells that arrange as single cells or in clusters of spindle cells arrayed in a storiform pattern. CASE: A 42-year-old male presented with a one-year history of an enlarging left forehead mass (lateral brow) that was adjacent to an old surgical scar. Fine needle aspiration revealed a low grade spindle cell neoplasm morphologically identical to a dermatofibrosarcoma protuberans excised 15 years earlier, indicating tumor recurrence. CONCLUSION: Distinguishing dermatofibrosarcoma protuberans from other spindle cell tumors and fibrohistiocytic lesions may pose significant challenges to the pathologist. However, in the appropriate clinical setting and applying strict diagnostic criteria, fine needle aspiration cytology is a reliable tool in establishing the diagnosis of this neoplasm.     

Iron Deposition after Transient Forebrain Ischemia in Rat Brain

In this study, we investigated the iron deposition in the cerebral cortex, hippocampus CA1 area and corpus striatum pars dorsolateralis in a rat model of cerebral ischemia. Forebrain ischemia was induced by four-vessel occlusion for 20 min. Using iron histochemistry, regional changes were examined from 1 to 8 weeks of postischemic recirculation. Neuronal death was demonstrated in pyramidal cells of the hippocampal CA1 area and in the dorsolateral part of the corpus striatum, which are known as areas most vulnerable to ischemia. Iron deposition in hippocampal CA1 area was coupled to delayed pyramidal cell death. Perl's reaction with DAB intensification revealed of the 1 week iron deposits in the CA1 area, which gradually increased and formed clusters by 8 weeks. In the corpus striatum, strong iron staining was observed in injured cellular layer pars dorsolateralis 1 week after recirculation. Granular iron was deposited in the cytoplasm of pyramidal cells in layers III and V of the frontal cortex after 2 weeks of recirculation. In contrast to the hippocampus and striatum, the cerebral cortex did not develop severe neuronal cell death and atrophy immediately after the ischemic insult, which suggest that the neuronal cell death in the cerebral cortex occurs extremely late.     

Fine needle aspiration cytology of the malignant variant of ossifying fibromyxoid tumor of soft parts: a case report

BACKGROUND: Ossifying fibromyxoid tumor (OFMT) of soft parts is a rare, recently defined, fibroosseous neoplasm, generally regarded as clinically benign; however, one-third of cases recur locally, and several malignant examples have been reported. Fine needle aspiration (FNA) cytology of the tumor is rarely described in the literature. We provide the first cytomorphologic study of the malignant variant. CASE: A 70-year-old man presented with an intramuscular mass in the right buttock. Computed tomography revealed ossification within the mass and multiple pulmonary nodules. FNA biopsy showed round and polygonal to spindled tumor cells, arrayed singly, cordlike or in small aggregates, with scattered dense stromal fragments and a slightly myxoid background. The nuclei showed significant pleomorphism accompanied by coarse chromatin with clumping, irregular contours, and one to two distinct nucleoli. The tumor cells were recognizable as sarcoma, with no evidence of high grade malignancy. The tumor was totally excised, histopathologically confirmed as the malignant variant of OFMT of soft parts, and immunohistochemically and ultrastracturally analyzed as of neural origin. CONCLUSION: The FNA specimen revealed that the cytomorphology was consistent with the histologic features of the malignant variant of OFMT, but several characteristic histologic parameters, such as multilobular proliferation and peripherally placed mature, bony trabeculae, were not reflected in the aspirates. Although FNA cytologic findings may be of limited diagnostic utility in OFMT, radiographic evidence of calcification/ossification suggests that OFMT should be subjected to differential diagnosis with fine needle aspiration biopsy of soft tissue tumors. Additional studies will be required for further clarification.