Expression of microtubule-associated protein tau by gastrointestinal stromal tumors.

The purpose of this work was to study the expression in gastrointestinal stromal tumors (GISTs) of various antigens, including the protein tau associated with enteric neuronal differentiation; to compare their expression with that of c-kit, known to be associated with interstitial cell of Cajal differentiation; and to correlate their expression with the observation of ultrastructural features of gastrointestinal autonomic nerve tumors. Twenty-six GISTs of the stomach and 16 GISTs of the small bowel were included in the study group. Thirty-five tumors served as controls. Tissue sections were immunostained with vimentin, CD34, desmin, specific smooth muscle actin, S100 protein, neuron-specific enolase, PGP9.5, neurofilament, bcl-2 oncoprotein, synaptophysin, chromogranin A, c-kit, and tau. Twenty-one of these tumors were also analyzed ultrastructurally. Of the 42 GISTs, 28 were predominantly spindled, 7 were predominantly epithelioid, and 7 were a mixture of epithelioid and spindle cells. Ten primary GISTs were classified as benign, 9 as borderline, and 23 as malignant. Metastatic dissemination was present at primary surgery in 1 case and eventually developed in 6 patients. Six disease-related deaths were counted. In normal submucous and myenteric plexuses of stomach and small bowel, ganglion cell bodies and nerve fibers strongly expressed tau. Twenty (76.9%) GISTs of the stomach and 12 (75%) of the small bowel expressed tau. Tau often showed intense, diffuse staining patterns in both spindled and epithelioid tumors. Ten (100%) of the 10 benign GISTs, 7 (77.8%) of the borderline GISTs, and 15 (65.2%) of the 23 frankly malignant GISTs expressed tau. Thirty-six GISTs expressed at least 2 different neuronal markers. A coexpression of the neuronal markers and c-kit was observed in 90% of GISTs. The expression of tau was observed in 12 of the 15 GISTs with dense core granules, considered as the definitive finding for a diagnosis of gastrointestinal autonomic nerve tumors. Ten of these also expressed c-kit; 9 were malignant. Tau also immunostained other intra-abdominal tumors, including neuroendocrine carcinomas, paragangliomas and desmoplastic round cell tumors. This immunohistochemical study shows that GISTs are specific tumors of the digestive tract and are nearly always characterized by simultaneous neuronal and interstitial cell of Cajal differentiation. Although the loss of tau expression is observed only in borderline and malignant tumors, its prognostic value is not clear cut.

[Cutaneous neural neoplasms--an update]. / Kutane Tumoren des Nervenhüllgewebes. Eine Ubersicht.

Until recently, benign cutaneous neural tumours which do not fulfil criteria for either neurofibrom or schwannoma often were lumped into the broad category of benign peripheral nerve sheath tumours (PNST). However, during the last years a number of new entities of neural tumours have been described, and advances in immunohistochemistry and electronmicroscopy have helped us to better understand the cytological differentiation in these neoplasms. The knowledge of these distinctive neoplasms is necessary in order to avoid diagnostic pitfalls and misdiagnosis of more aggressive neoplasms. These distinctive lesions include: neurothekeoma, which can divided into classical myxoid and cellular types showing characteristic histological and immunohistochemical features. Typical neurothekeoma (nerve sheath myxoma) is a lobular or nodular dermal neoplasm composed of plump spindled or stellated, S-100 positive tumour cells set in a maxoid stroma. In contrast, cellular neurothekeoma is characterized as an ill-defined dermal neoplasm composed of concentric nests and fascicles of spindle-shaped and epithelioid tumour cells, which are S-100 negative but stain positively for NKIC3. The evidence of intermediate forms of neurothekeoma showing features of ordinary hypocellular neurothekeoma and cellular neurothekeoma, as well as ultrastructural studies, emphasize that both variants represent a spectrum of neurothekeoma; solitary circumscribed neuroma ("palisaded encapsulated neuroma") manifests mainly as a skin-colored or pink papule or nodule, and is most often located on the face. Histologically, solitary circumscribed neuroma is a well-circumscribed round or ovoid dermal neoplasm composed of interwoven fascicles of schwann cells, which stain positively for S-100 protein and numerous neurofilament positive axons surrounded partly by fibroblasts and EMA-positive perineural cells; perineurioma is a rare well-circumscribed neoplasm which occurs mainly in subcutaneous tissue and only rarely in the dermis and in deep soft tissues. Perineurioma is composed of elongated bipolar spindle-shaped tumour cells which are arranged in storiform, whorled, linear or lamellated growth patterns, The tumour cells stain positively for vimentin and EMA, and for CD 34 in a number of cases, but lack positivity for S-100 protein, neurofilament and desmoplakin. In addition unusual forms of schwannoma (cellular schwannoma, solitary plexiform schwannoma, melanotic schwannoma) and neurofibroma ("atypical" (bizarre) neurofibroma, diffuse neurofibroma, epithelioid neurofibroma) are briefly discussed.

Gastrointestinal autonomic nerve tumor (plexosarcoma): report of a case with fine needle aspiration biopsy and histologic, immunocytochemical and ultrastructural study.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) encompass a large group of mesenchymal neoplasms that display common cytologic spindle-shaped morphology on light microscopy. Immunocytochemical and ultrastructural studies can demonstrate several patterns of differentiation. CASE: A 70-year-old male presented with two intraabdominal small bowel masses. The cytopathologic features of a fine needle aspiration biopsy (FNAB) included plump spindle cells in densely populated aggregates or in a fasciculated pattern, without significant pleomorphism. An epithelioid component in a lobular arrangement with abundant, eosinophilic cytoplasm was also noted. The nuclei were vesicular, with a very evident, eosinophilic nucleolus and finely distributed chromatin. Groups of loosely cohesive cells with slender, dendritic-like cytoplasm were evident. Immunocytochemical study of the embedded, fine needle aspirated fragments of the neoplasm demonstrated immunoreactivity for vimentin and neuron-specific enolase. Cytokeratin immunoreactivity or muscular, vascular, neuroendocrine or nerve sheath differentiation failed to be demonstrated. The cytologic and immunocytochemical findings correlated well with the histologic features of the neoplasm. The morphologic diagnosis was confirmed by ultrastructural study. CONCLUSION: FNAB and immunocytochemistry can be valuable in making the correct diagnosis between gastrointestinal stromal tumors.

Gastro-intestinal stromal tumors: an ultrastructural reinterpretation of the clear cell component.

The histology, immunohistochemistry and ultrastructure of six gastro-intestinal stromal tumors of the stomach (GSTs) showing a focal to diffuse clear cell component are reported. At light microscopy, all GSTs had typical histopathological features with one case additionally displaying stromal myxoid changes and scattered multinucleated giant cells. Immunohistochemically, 6 of 6 GSTs stained positive for vimentin, 2 of 6 for smooth muscle specific actin and 1 of 6 for desmin. At electron microscopy, GSTs showed microfilaments with focal densities as well as other smooth muscle features, such as subplasmalemmal linear densities and foci of external lamina. Ultrastructural appearances of tumor cells with clear cell features showed these not to be an artifact of fixation, but the expression of an unusual cytophagocytic activity. Inclusions of auto- and heterophagocytic nature were found responsible for the origin of the large, mostly lipidic vacuoles which displaced cell nuclei peripherally in a signet-ring fashion. It is concluded that such previously unrecognized features are ultrastructural aspects of GSTs with smooth muscle differentiation.

Gastrointestinal autonomic nerve tumours and their separation from other gastrointestinal stromal tumours: an ultrastructural and immunohistochemical study of seven cases.

Gastrointestinal stromal tumours (GIST) represent a heterogeneous group whose classification frequently requires ultrastructural and immunohistochemical studies. In a retrospective study of the ultrastructural findings of 24 gastrointestinal stromal tumours, whose light microscopic study has yielded ambiguous results and in which accurate diagnosis had required ultrastructural support, seven were found to have the characteristics of gastrointestinal autonomic nerve (GAN) tumours. In all of them the diagnosis was based on the presence of dendritic processes with dense neuroendocrine granules. Immunohistochemically, the seven tumours were negative for smooth-muscle markers. All stained positively for vimentin. NSE, chromogranin, and synaptophysin were positive in most of them, while S-100 protein was positive only in two cases. We present the ultrastructural and immunohistochemical features of seven GANT against the background of the GISTs of our series. We conclude that GAN tumours cannot be diagnosed by light microscopy alone but this tumour group displays characteristic electron microscopic and immunohistochemical features and appears to represent a distinct type of GIST.

Gastrointestinal autonomic nerve tumor: a case report with electron microscopic and immunohistochemical analysis and review of the literature.

A case of an adolescent girl with metastatic gastric stromal tumor is described. There were three metastatic nodules in the liver at the time of the admission. A subtotal gastrectomy was performed. The tumor had distinctly nodular appearance and was composed of a variety of cells suggestive of smooth muscle differentiation. Electron microscopy revealed cytoplasmic neural processes and densecore neurosecretory granules. Immunohistochemistry showed positive neuron-specific enolase, synaptophysin, and chromogranin A in some of the tumor cells. Similar findings in the primary tumor and its liver metastases indicated a primitive neural differentiation and enabled us to classify the lesion as a gastric autonomic nerve tumor. No other tumors that would suggest that the gastric lesion is a part of Carney's triad were detected. The child was treated with chemotherapy but the liver metastases did not change significantly. She is alive with unresectable liver metastases 10 months after the gastrectomy.

Gastrointestinal autonomic nerve tumors: a clinicopathological, immunohistochemical and ultrastructural study of 10 cases.

Gastrointestinal Autonomic Nerve Tumors (GANTs) are an underrecognized group of gastrointestinal stromal tumors (GISTs) putatively arising from the neural plexuses of the bowel wall. Approximately 24 cases have been previously reported. Their histogenesis, malignant potential, morphology and phenotypic features are not well defined. We present details of 10 GANTs iterating features, predominantly ultrastructural, allowing distinction from other GISTs. Clinical details are: sex-7M, 3F; age range 31-79 yrs, mean 53; symptoms/signs--abdominal pain 3, GI bleeding 3, mass 2, anemia 2. Follow-up ranged from 1-102 mths, mean 29. Seven tumors involved the small intestine and 3 were gastric. Tumor size ranged from 30-160 mm, mean 79. They were solid and cystic, often transmural and usually involved mesentery and retroperitoneum. Spindled and epithelioid cells were "compartmentalized" by a branching microvasculature. Eosinophilic, PAS positive stromal globules were prominent. Paraffin immunostaining results were (number positive/total): vimentin (8/9), NSE (10/10), S100 protein (6/10), neurofilament protein (0/9), synaptophysin (3/9), desmin (2/9, focal), smooth-muscle actin (0/9). Ultrastructural diagnostic features were elaborate, branching cytoplasmic processes containing microtubules, intermediate filaments and varying numbers of neurosecretory granules. Characteristic features were elaborate smooth endoplasmic reticulum enmeshed with intermediate filaments, pleomorphic mitochondria with lamellar cristae, mitochondrial-RER complexes, confronting RER cisternae, and circumscribed collections of stromal "skeinoid" fibres. There were no features of smooth muscle, Schwannian or perineurial differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrointestinal autonomic nerve tumor presenting as high-grade sarcoma. Case report and review of the literature.

Gastrointestinal autonomic nerve (GAN) tumors, also known as plexosarcomas, are a rare distinct subtype of the gastrointestinal stromal tumors. These tumors are usually histologically low-grade, epithelioid or spindle-cell neoplasms that can be distinguished from the other gastrointestinal stromal tumors on the basis of their unique ultrastructural features. A 66-year-old female presented with a histologically high-grade sarcoma of the small bowel. Ultrastructural studies showed features of a GAN tumor. The light microscopic and ultrastructural features are described. The tumor cells gave strong, diffuse staining for vimentin and synaptophysin, and weak focal staining for neuron-specific enolase and S100. While usually presenting as low-grade neoplasms on histologic examination, this case demonstrates that GAN tumors should be considered in the differential diagnosis of a histologically high-grade sarcoma of the gastrointestinal tract, especially when evidence of smooth muscle, peripheral nerve sheath, or neuroblastic origin is not forthcoming.

CD-34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions.

The pattern of CD-34 antigen (human progenitor cell antigen) immunoreactivity was studied within normal nerve, and a variety of nerve sheath and neuroectodermal tumors. Besides normal nerves, 111 soft tissue tumors were studied, including 17 neurofibromas, 10 neurilemomas, 12 malignant peripheral nerve sheath tumors, 1 melanocytic schwannoma, 21 fibroblastic lesions, 31 fibrohistiocytic lesions, seven neuroectodermal lesions, and 10 miscellaneous tumors. CD-34-positive dendritic cells were consistently identified within the endoneurium of normal nerve, all neurofibromas, dermatofibrosarcomas, and Antoni B (but not Antoni A) areas of neurilemomas. CD-34 was not expressed in the majority (eight of 10 cases) of malignant peripheral nerve sheath tumors. CD-34 was also lacking in all fibroblastic lesions (nodular fasciitis, fibromatosis, keloid, fibrosarcoma) and in neuroectodermal tumors that are not generally considered to show true nerve sheath differentiation (neurotropic melanoma, clear cell sarcoma, neuroepithelioma). We conclude that CD-34 (or a closely related epitope) defines a normally occurring nerve sheath cell that appears to be cytologically and immunophenotypically distinct from a fibroblast and conventional Schwann cell. The antigen can also be localized to benign nerve sheath tumors, but tends to be lost in malignant ones. The consistent presence of CD-34 within all 13 cases of dermatofibrosarcoma protuberans can be used as evidence in support of the view that these lesions are variants of nerve sheath tumors, and distinct from benign fibrous histiocytomas which consistently lack the antigen. Finally, expression of CD-34 by one of three giant cell fibroblastomas reinforces the close relationship between this tumor and dermatofibrosarcoma protuberans.

Gastrointestinal autonomic nerve tumors. A clinicopathological, immunohistochemical, and ultrastructural study of 12 cases.

The gastrointestinal autonomic nerve tumor (GAN tumor) is an uncommon stromal tumor of the intestinal tract and retroperitoneum first described by Herrera and associates in 1984. Distinction of GAN tumors from other gastrointestinal stromal tumors is based on electron microscopic findings. Thus far there have been 12 reported cases. We present an additional 12 GAN tumors, identified by us during 4 years. There were seven male and five female patients and they ranged in age from 10 to 85 years (mean: 58 years). Sites of the tumors were stomach (three), jejunum (two), ileum (four), mesentery (one), and retroperitoneum (two). Eight of the tumors measured > 10 cm in greatest dimension. Usually well circumscribed, the neoplasms were tan to light pink, sometimes hemorrhagic, and soft. There was a variety of histologic patterns including fascicles, palisades, and whorls. Mitotic activity varied from 0 to 23 mitosis per 10 high-power fields (HPF). Using a panel of 10 immunohistochemical stains, only vimentin was consistently positive. There was neuron-specific enolase reactivity in six and S-100 protein reactivity in two cases. All muscle markers were negative. Ultrastructural studies showed neuron-like cells with long axonic cytoplasmic processes ending in bulbous synapse-like structures containing dense-core neurosecretory granules and clear vesicles. Basement membrane was absent. These features are reminiscent of ganglia of the intestinal autonomic nervous system. The patients were followed for 5-125 months (mean of 26 months). Tumor recurred or metastasized to the liver in seven patients (58%) and four patients died with tumor. There were correlations between tumor size (> 10 cm), mitotic count (at least five per 10 HPF), and aggressive behavior.

Nuclear/cytoplasmic ratio correlates strongly with survival in non-disseminated neuroendocrine carcinoma of the lung.

In order to verify whether quantitative morphological indices of neuroendocrine carcinoma of the lung may help to predict survival, 47 biopsies (from 37 males and 10 females; 16-82 years of age) were studied by light microscopy. Areal fractions of nuclei, cytoplasm, stroma, and blood vessels were determined using a standard point counting method. The counts were made in six non-coincident microscopic fields in each case, and the areal fractions of nuclei, of the entire tumour cell, stroma, blood vessels and the nuclear/cytoplasmic ratio were computed. In a multivariate linear regression analysis, survival in months after biopsy was considered the dependent variable of age and of all morphometric parameters listed above. The significance level was set at 5%. For all patients (disregarding staging) survival was negatively correlated (P < 0.001, multiple r = 0.5435) with age and nuclear/cytoplasmic ratio. When only patients with disease confined to the thorax (stages I, II and III) were taken into account, the accuracy of the function predicting survival increased considerably (P = 0.004, multiple r = 0.7957). The use of simple stereological methods, therefore, proved to be of value in predicting survival in patients with neuroendocrine carcinomas of the lung.

Primitive neuroectodermal tumors of the uterus: a report of four cases.

Four cases of primitive neuroectodermal tumor (PNET) of the uterine corpus are reported, bringing the total number of reported PNETs in this site to seven. The four women were in their seventh decade of life and presented with abnormal vaginal bleeding and, in two cases, an enlarged uterus. The patients underwent total or subtotal abdominal hysterectomy and bilateral salpingo-oophorectomy and, in one patient, pelvic lymphadenectomy. Three patients received postoperative radiation therapy, chemotherapy, or both. Gross examination revealed fleshy polypoid masses filling the endometrial cavity and, in two cases, deeply invading the myometrium. Histologic, immunohistochemical, and, in two cases, ultrastructural examination revealed typical PNETs that exhibited variable degrees of neural, glial, ependymal, and medulloepithelial differentiation. Two PNETs were admixed with other neoplasms: in one case a grade I endometrial adenocarcinoma and in the other a low-grade endometrial stromal sarcoma. The prognosis of the tumors was related to their stage: two patients with stage I tumor were alive with no evidence of disease at 5 and 6 years, whereas two patients with stage III or IV tumor died of tumor at 6 and 12 months. Although it has been suggested that uterine PNETs may be derived from displaced germ cells or implanted fetal tissues, evidence provided by this study, including the advanced ages of the patients and an admixture with neoplasms of unquestioned müllerian origin, suggests a müllerian origin for these tumors in at least some cases.

Gastrointestinal autonomic nerve tumours: a case report with ultrastructural and immunohistochemical studies.

A case of gastrointestinal autonomic nerve tumour with light microscopic, immunohistochemical and ultrastructural examination is reported. The tumour was composed of spindle cells or large cells with clear cytoplasm and showed intense staining for vimentin and focal staining for neuron-specific enolase, chromogranin, synaptophysin, gastrin, P substance and S-100 protein. Ultrastructural examination showed long processes with dense core granules and the absence of features characteristic of other gastrointestinal stromal tumours. In addition we noted small traces of basal lamina and the absence of synaptic vesicles. It seems that the biological behaviour of gastrointestinal autonomic nerve tumours is aggressive but there are too few reports on which to conclude anything about their prognosis. Our findings suggest that tumour has a neuroectodermal differentiation.

Polysialic acid as a marker of both immature and mature neural tissue in human teratomas.

The neural cell adhesion molecule (NCAM) is involved in cell-cell interaction during neural development. We employed a monoclonal antibody directed against the long chain polysialic acid moiety of NCAM to evaluate its usefulness as a marker of primitive neural elements in teratomas. This marker was compared with other neural markers, S-100, glial fibrillary acidic protein (GFAP), neurofilament protein (NFL), nerve growth factor receptor (NGFR), as to its effectiveness in labeled neural tissue in human teratomas. The anti-polysialic acid antibody was the only reagent that consistently marked all types of neural tissue, both mature and immature in these lesions. Immature neural elements alone have prognostic significance in teratomas. Our results indicate that anti-polysialic acid antibodies are the most sensitive and useful markers of immature neural elements in these lesions.

Soft tissue neoplasma of the mediastinum.

Among all neoplasms of the mediastinum, those composed of mesenchymal elements, and arising primarily in mediastinal soft tissue, are the least common group of tumors discussed in this issue of Seminars. Apart from tumors of nerve sheath, neuroectoderm, adipose tissue, and lymphatic vessels, few of them will comprise a significant part of the surgical pathologist's practice. Yet each poses two important clinical problems: the recognition of visceral-associated (as opposed to primary soft tissue) lesions, and the exclusion of metastases from an extrathoracic site. In this review, the histologic, immunohistochemical, and ultrastructural features that characterize mediastinal soft tissue tumors will be emphasized. Clinical aspects of these lesions are also discussed, particularly as they may relate to the aforementioned clinical questions.

Gastrointestinal autonomic nerve tumor.

The article describes a case of gastrointestinal autonomic nerve tumor, which is histogenetically related to the gastrointestinal autonomic plexus (hence the name plexosarcoma). This rare and only recently recognized tumor of the gastrointestinal tract appears to have significant prognostic implications. This tumor cannot be diagnosed unequivocally by light microscopic and immunocytochemical examinations but shows characteristic electron microscopic features. The present case occurred as a gastric primary tumor and exhibited a light and electron microscopic picture similar to the one described in previous reports: areas of spindle-shaped and epithelioid cells, cytoplasmic processes with dense-core granules, and cytoplasmic intermediate filaments. Ultrastructural characteristics diagnostic of other gastrointestinal tumors, such as those originating from smooth muscle, Schwann cell, or endocrine cell types, were absent. Immunocytochemically, the tumor was diffusely positive for vimentin and neuron-specific enolase and focally positive for neurofilament triplet protein (NFTP) 160. Negative staining was observed for NFTP 200, S-100 protein, desmin, somatostatin, chromogranin, keratins (AE1/AE3), and glial fibrillary acidic protein. Although gastrointestinal autonomic nerve tumor has been reported to have a deceptively low-grade malignant appearance by light microscopy, it follows an aggressive clinical course. This tumor showed a much higher mitotic rate (one mitosis per high-power field) than the rates of tumors reported previously. Moreover, it occurred in a much younger patient (20 years of age) compared to previously reported cases (45 to 66 years of age), with the exception of one other case (16 years of age).