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Twenty-two cases with gastrointestinal stromal tumors (GISTs) have been studied, sized from 2 cm to invasive gigantic tumors and also from low to high degree of malignancy. The altering of the form and the size of the nucleus is a reference point of malignancy, being used in the histological grading of many types of tumors and also as an appreciating parameter of the tumoral prognosis, with a high degree of accuracy in the colorectal, uterine, prostatic or ovarian cancers, as it was pointed in the previous researches. The aim of this study is to evaluate the dimensional characteristic of the nuclei and the mitosis in GIST with a cholic and gastric localization, attempting a quantitative differentiation of the two tumors, by studying the following aspects: nuclear dimensions, mitotic activity index and the mitotic density. The results of the proliferative activity quantification (mitotic activity index and mitotic density) have shown that this can be a decisive criterion for the precocious appreciation of the evolution. The most important morphological criterion with a predictive role is the mitotic activity index, but is recommended to be applied correlated with the size and the localization of the tumor. Although various nuclear morphometry studies in different types of malignant tumors have been performed, the data in gastrointestinal stromal tumors is scarce and only few similar studies have been reported in the specialty literature; from this point of view, the present study is new and original and is also trying to point out that even with GIST, such analysis and prognosis is as valuable as in any other malignant diseases.

Gastrointestinal stromal tumours (GIST) are rare tumours of the gastrointestinal tract. Dealing with these tumours requires a profound knowledge of the nature of the lesions and their malignant potentials. Modern ultrasound techniques provide the necessary tools to give the clinician the information he needs to diagnose and treat the patient. This article reviews the actual pathophysiological knowledge of GIST and provides a broad spectrum of ultrasound findings to introduce the reader into modern ultrasound investigation methods of subepithelial tumours. It covers the transcutaneous as well as the endoscopic ultrasound approach. Different conditions of GIST like the low risk or high risk form as well as the metastatic form will be discussed in diagnosis and treatment with plenty of examples. Special attention is paid to contrast-enhanced ultrasound techniques and elastography from the transcutaneous as well as the endoscopic route. Other diagnostic methods like CT, MRI and PET CT are additionally reviewed and their role in clinical practice is compared with that of ultrasound. The aim of the article is to introduce the reader into the new ultrasound techniques and special diagnostic behaviour of GIST and outline clinical pathways to deal correctly with different stages of the disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

Endomicroscopy is a newly developed imaging modality, which provides in vivo histology during ongoing endoscopy. This review characterizes the currently available endomicroscopic systems and reflects the clinical value of endomicroscopy for different diseases. Endomicroscopy can be used to discover histology of the mucosal layer at cellular and subcellular resolution. Furthermore, endomicroscopy can be used to observe physiologic and pathophysiologic changes, which offer a newly available insight into the pathogenesis of different diseases. The diagnostic possibilities of endomicroscopy are extensive and highly valuable for every day practice. However, the era of endomicroscopy has just started and it can be anticipated that its role will significantly increase in the future.

Skeinoid fibers are globular, brightly eosinophilic periodic Schiff stain (PAS)-positive extracellular collagen deposits commonly seen in gastrointestinal stromal tumors (GIST) of the small bowel. However, smooth-surfaced hyaline globules are occasionally encountered in leiomyomatous GI neoplasms and may be mistaken for true skeinoid fibers. We investigated a total of 93 histologically and immunohistochemically well-characterized true smooth muscle neoplasms of the GI tract for the presence of hyaline globules. A variable number of PAS-positive intracellular and interstitial hyaline globules were detected in all benign paucicellular leiomyomas of the muscularis mucosae (n=72) and the muscularis propria (n=14) irrespective of tumor size and site, but in none of leiomyosarcomas (n=7) and cellular leiomyoma (n=1). In addition, similar findings were rarely seen in the adjacent muscularis propria. Similar to surrounding tumor cells, hyaline globules expressed desmin, alpha-SMA, and h-caldesmon, but were negative for CD117 and CD34. Ultrastructural examination revealed altered filamentous material in different stages of degeneration with variably condensed matrix and occasional peripheral condensation suggestive of calcification. True skeinoid fibers were not detected. The above findings are consistent with a multistep degenerative phenomenon affecting individual smooth muscle cells in paucicellular GI leiomyomas. Awareness of this finding would prevent misinterpretation as GIST, particularly in small biopsies.

Purpose: Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined., Experimental Design: We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR., Results: Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin., Conclusions: EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.

Objective: Primary to search the rule of pre-operative chemotherapy and suitable duration for it by investigating the changes of calpain content and activity after 5'-deoxy-5-fluorouridine (5'-DFUR) per oral administered pre-operatively in different time. Further to investigate the mechanism of chemotherapy., Methods: Seventy-three patients with gastrointestinal malignant tumors were divided into 4 groups by the time of 5'-DFUR (600 approximately 1200 mg/d) by oral administration before operation, group A, 3 days, 27 cases; group B, 1 week, 22 cases; group C, 2 weeks, 15 cases; group D, 2 months, 9 cases. And group E, control group, had 24 patients with gastrointestinal malignant tumors at the same term. The patients above all had not received the other chemotherapy and radiotherapy. Western blot and immunoelectron microscopy were employed to detect the expressing levels and activities of calpain in tumor tissues of different groups., Results: Electronic microscopic examination showed gold granula mainly on the membranes of mitochondria of tumor cells to groups after chemotherapy. And the tumor cells of group A were mildly damaged. Besides that, serious injury for tumor cells of group B could be seen, and the phenomena were common in group C. But the damages to tumor cells of group D were mainly about mildness. The results of immunoelectron microscopy revealed that the contents of calpain increased following the time of chemotherapy prolonging, and peaked in group C. Still more, there was no significant difference for the results between group C and group D. The changes of calpain activities observed by western blot had the same tendency as the results from immunoelectron microscopy (r = 0.86, P < 0.0001)., Conclusions: 5'-DFUR via oral administered pre-operation could have anti-cancer effect through calpain. And the effect might be strongest in 2 weeks also after chemotherapy.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract (GIT). Although interstitial cells of Cajal has been suggested as origin of this tumor, the cytological and ultrastructural features of GISTs are heterogeneous and unclear. A total 10 cases of normal gastrointestinal tissue (control), 13 GISTs of the stomach (8), small intestine (3), mesocolon (1) and liver (1), and 2 gastrointestinal autonomic nervous tumor (GANT) of small intestine were ultrastructurally studied. Normal interstitial cells of Cajal (ICC) were abundantly present around the myenteric plexuses or individually scattered through the wall of GIT. ICC was characterized by slender cytoplasmic processes, well-developed endoplasmic reticulum (ER), mitochondria, Golgi apparatus, caveolae and intermediate filaments. The GISTs and GANTs had overlapping ultrastructures. The most common and important ultrastructural features of GISTs were rich villous cytoplasmic processes, dispersed intermediate filaments and abundant SER, and those of GANTs were neurosecretory granules and skenoid fibers. Compared with ICC, the GISTs and GANTs had remarkably reduced caveolae and gap junctions. Our study suggested that ultrastructural analysis gives much information to investigate lineage differentiation of neoplastic cells and make a differential diagnosis of these tumors from other mesenchymal tumors and between GISTs and GANTs.

A case for primary gastrointestinal stromal tumor (GIST) is described with reference to its ultrastructural characteristics and mutation within the exon 11 of c-kit gene. A forty-seven years old woman complaining of dysphasia was examined by endoscopy, which depicted a submucosal tumor (70 mm in diameter) with ulcerations at the fundus of the stomach. Histopathologically, the tumor cells had large nuclei and eosinophilic cytoplasm and were frequently during mitosis phase. The tumor cells were immunopositive for KIT, CD 34 and vimentin, suggesting their fibroblast-like characteristics. In contrast, desmin and S-100, a smooth muscle and an enteroglial marker, were not immunopositive within the cells. At least 30 % of the tumor cells possessed MIB-I and 20 % of them possessed p53, which are compatible with fast development of the tumor. By electron microscopy, the tumor cells possessed large oval nuclei, abundant mitochondria, caveolae and smooth endoplasmic reticulums, while no gap junctions were seen on the cells: The tumor cells thus possessed interstitial cells-like characteristics at least in part. DNA mutation search for the tumor cells however realized no gain-of-function mutation within the exon 11 of the c-kit gene, suggesting existence of other mechanism for neoplasmic growth of the tumor cells classified as gastrointestinal stromal tumors.

Background & Objective: Pyrimidine nucleoside phosphorylase (PyNPase) exists mainly in tumor tissues.5'-deoxy-5-fluorouridine(5'-DFUR) can decrease its level in tumor tissues. However, the effect of preoperative oral 5'-DFUR on PyNPase level in the different time after administration has not been reported. This study was designed to investigate the suitable duration of preoperative chemotherapy through observing the changes of PyNPase levels in gastrointestinal malignant tumors after preoperative oral administration of 5'- DFUR in different duration., Methods: Seventy-three patients with gastrointestinal malignant tumors were divided into four groups by the duration of preoperative oral 5'-DFUR (600-1,200 mg x d(-1)): group A, three days, 27 cases; group B, one week, 22 cases; group C, two weeks, 15 cases; group D, two months, 9 cases. Meanwhile, group E, control group, had 24 inpatients with gastrointestinal malignant tumors at the same term. All the above-mentioned patients did not receive the other chemotherapy or radiotherapy. The changes of PyNPase levels in tumor tissues of different groups were tested using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC), etc., Results: (1)Under electron microscope, there were many irrecoverable, lethal changes in tumor cells of group C. The outlines of the tumor cells were normal under light microscope, and more fibroconnective tissues were seen only in the stroma of group D. (2)The expressing levels of PyNPase mRNA and protein production in tumor tissues reduced obviously in group A (0.79+/-0.08, 19.26+/-1.65), and decreased most obviously in group C (0.43+/-0.07,5.91+/-1.45) comparing with group E (0.95+/-0.09, 29.34+/-1.82). However, there was no significant difference between group C and group D (0.42+/-0.04, 5.36+/-1.19) for the levels of PyNPase mRNA and protein production. The correlation coefficient between the levels of PyNPase mRNA and protein in tumor tissues of different group was r=0.92(P< 0.0001)., Conclusion: 5'-DFUR by oral administration before operation might destroy gastrointestinal malignant tumor cells. As the duration prolonged, the content of PyNPase in tumor tissues decreased progressively, being lowest level in two weeks after chemotherapy. So two-week duration might be suitable for the treatment.

Six cases are reported of an osteoclast-rich tumor of the gastrointestinal tract that should be segregated from GIST. Five of the cases were located in the small bowel and one in the stomach. The age of the patients ranged from 13 to 37 years. The tumors behaved aggressively, with metastases to regional lymph nodes, liver, and other intra-abdominal sites. Microscopically, the tumor cells were medium-sized, predominantly oval, relatively monomorphic, diffusely immunoreactive for S-100-protein, and negative for CD117, CD34, HMB-45, and Mart-1. They were admixed with scattered osteoclast-like, multinucleated giant cells which were S-100-protein negative and KP1-positive. One case studied cytogenetically had the karyotype 46XX t(12;22)(q13;q12). The cases here reported are interpreted as examples of a distinctive type of gastrointestinal neoplasm which shares some features with clear cell sarcoma of soft parts (melanoma of soft parts), including in one case the chromosomal translocation that is characteristically associated with that entity.

Rhabdoid tumor, first described in kidneys of infants and children, is an aggressive tumor that has been reported in several extrarenal locations. Gastrointestinal tumors with rhabdoid features are extremely rare. The effect of the rhabdoid phenotype on the aggressiveness of gastrointestinal tumors remains unclear. We present four cases of rhabdoid tumors of the gastrointestinal tract involving the esophagus, stomach, and small intestine and discuss the clinicopathologic, immunohistochemical, and ultrastructural features. In the four cases reported herein, the patients' ages ranged from 52 to 73 years, and tumor size ranged from 3.8 to 13 cm in greatest dimension. The noncohesive rhabdoid cells exhibited an eccentric nucleus with a paranuclear inclusion, which was shown by electron microscopic examination to be composed of intermediate filaments. On immunohistochemical staining, the tumor cells were positive for vimentin and cytokeratin. Three patients developed distant metastasis shortly after diagnosis and died of disease within 2 to 10 months after initial presentation. A retrospective review of outcomes of the current cases and previously published literature showed that 12 (75%) of the 16 patients died within 6 months of presentation. Recognition of the rhabdoid phenotype in gastrointestinal tract neoplasms is important because this feature is associated with poor prognosis and unresponsiveness to conventional therapy., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Gastrointestinal stromal tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunocytochemically, and genetically differ from leiomyomas, leiomyosarcomas, and schwannomas. GISTs derive from the interstitial cells of Cajal and, in addition to variable expression of smooth muscle and neural markers, they characteristically express CD34 and CD117. The cytological appearance, including immunocytochemical and mutational analysis of c-kit gene in primary GIST has been well described. To our knowledge, only two cases of metastatic GIST diagnosed by fine-needle aspiration (FNA) have been reported. We illustrate three cases of metastatic GIST in the liver. Two cases had no prior history of gastrointestinal tumor and the third case had a 4-yr previous history of duodenal tumor. Consistent immunocytochemistry and ultrastructual studies supported the diagnosis of GIST. We emphasize that in the appropriate clinical and radiological setting, a confident diagnosis of GIST can be established by FNA of metastatic lesions., (Copyright 2002 Wiley-Liss, Inc.)

Eighty-two mesenchymal tumors of the gastrointestinal tract were examined by electron microscopy for the purposes of subtyping for diagnostic precision and of understanding cellular differentiation. Tumors were subclassified into leiomyoma/leiomyosarcoma, tumors of the interstitial cell of Cajal (equivalent to traditionally defined GISTs [Miettinen et al. Hum Pathol. 1999; 30:1213-1220; Mod Pathol. 2000; 13:1134-1142]), gastrointestinal autonomic nerve tumors (GANTs), and fibroblastic and myofibroblastic tumors, using criteria from the literature. Leiomyoma/leiomyosarcoma were diagnosed by myofilaments, attachment plaques, plasmalemmal caveolae, and lamina; GIST by processes or cell bodies full of intermediate filaments, solitary focal densities amid intermediate filaments, attachment plaques with incomplete lamina, scarce myofilaments, and smooth endoplasmic reticulum; GANTs by neuroendocrine granules, cell bodies/processes full of intermediate filaments (more rarely microtubules), and smooth endoplasmic reticulum; fibroblastic/myofibroblastic tumors by abundant rough endoplasmic reticulum, myofilaments, and fibronexuses. Seventy-three tumors (89%) were successfully subclassified, as 5 leiomyoma/leiomyosarcoma (6%), 36 GISTs (44%), 22 GANTs (27%), 10 fibroblastic and myofibroblastic tumors (12%). Results indicated overlap between poorly differentiated leiomyosarcoma and GIST, and between GIST and GANT. GANT is emphasized as a neuronal tumor identifiable by electron microscopy, and thereby distinguishable from GIST.

Gastrointestinal stromal tumors (GISTs) with neurogenic differentiation, also referred to as "gastrointestinal autonomic nerve tumors (GANTs)," form an ultrastructurally distinctive subgroup of mesenchymal neoplasms of gastrointestinal tract. Cytogenetic and molecular data of these tumors are limited. In the current study, c-KIT gene sequenc-ing analysis, comparative genomic hybridization (CGH), and interphase fluorescence in situ hybrid- ization (FISH) analysis, utilizing chromosome 14- and 22-specific probes, were performed on five primary ultrastructurally confirmed GANTs. FISH and CGH analysis revealed loss of a whole or part of chromosome 14q in two tumors and of chromo- some 22q, with the common overlapping area of loss at q13, in all five tumors evaluated. c-KIT mu- tations were found in all cases; three tumors carried point mutation and/or deletions of exon 11, and in two tumors, insertion in exon 9 was found. These findings suggest that accumulated genetic changes contribute to the pathogenesis of GANTs and that 22q13 loss may be a characteristic feature of these tumors.

Gastrointestinal stromal tumors (GISTs) represent an enigmatic group of lesions of uncertain phenotype and biologic potential. Although earlier studies suggested smooth muscle cells, schwann cells, or neuronal differentiation, more recent evidence indicates that these tumors show phenotypic features that are similar to the interstitial cells of Cajal. Recently, investigators have begun to evaluate these lesions in a site-specific manner and have found that, in addition to morphologic differences between them, their biologic behavior also appears to be linked to their anatomic location. Many of these studies have emphasized the histologic and immunophenotypic features of GISTs in relation to their sites of origin, however, their site-specific ultrastructural characteristics have received little attention in the literature. In this study, we evaluated 34 GISTs (15 gastric, 12 small intestinal, 4 colonic, and 3 omental) for a variety of ultrastructural features in an effort to identify site-specific similarities and differences. Tumors predominantly composed of epithelioid cells were more commonly seen in gastric (60%) and omental (67%) tumors than in those of the small intestine (33%) and colon (0%). Cytoplasmic filaments and intercellular junctions were commonly seen in tumors from all locations, the filaments frequently forming paranuclear aggregates in the epithelioid cells. Tumors from all sites were composed of cells with surface filopodia and interdigitating cell processes, but in tumors of the stomach and omentum the filopodia were usually short and minimally intertwined, whereas those of small and large intestinal GISTs were characteristically long and complex. Basal lamina, though poorly formed, was present only in tumors of gastric and omental origin (13% and 67%, respectively). Pinocytotic vesicles were also seen in tumors from these sites (33% of gastric tumors and 67% of omental lesions) as well as those of the small intestine (17%) and the colon (25%). None of the gastric or omental tumors had microtubules; they were, however, seen in small intestinal (33%) and colonic (25%) stromal tumors. Skenoid fibers were seen in 33% of small intestinal GISTs and 1 metastatic gastric GIST. Overall, gastric and omental tumors have better developed features of myogenic differentiation and have blunt filopodia and minimally intertwined cell processes. Indeed, these 2 groups are indistinguishable ultrastructurally, raising the possibility that the genesis of omental GISTs is similar to that of gastric stromal tumors. Small intestinal stromal tumors have characteristic interdigitating cell processes and numerous elongate filopodia-like structures harboring intercellular junctions as well as microtubules and extracellular skenoid fibers. The constituent cells in colonic stromal tumors, while more reminiscent of small intestinal stromal, were frequently more primitive in appearance. In conclusion, GISTs from different anatomic locations share many overlapping ultrastructural characteristics; however, a few features are distinctive. It is hoped that these findings will aid in their recognition and contribute to the classification of this heterogeneous group of neoplasms.

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., (Copyright 2001 by W.B. Saunders Company)

Eleven gastrointestinal neoplasms from 10 aged horses and 1 pony were examined grossly, his tologically, immunohistochemically, and (in two cases) ultrastructurally. Clinical signs were associated with two neoplasms, and the other nine tumors were incidental findings at laparotomy or necropsy. The neoplasms were solitary (9/11) or multifocal (2/11), well demarcated, serosal or mural masses of stomach (1), jejunum (1), ileum (3), cecum (5), and/or colon (2). Microscopic examination revealed discrete spindle cells arranged in compact patterns with fascicles and whorls or cribriform pattern with fascicles and rare palisades, often with a myxoid interstitial matrix. Three tumors infiltrated between the muscularis interna and the muscularis externa at the myenteric plexi. All neoplasms were vimentin positive, 3/11 were S-100 positive, 2/11 were muscle actin positive, and no neoplasm was positive for glial fibrillary acid protein, desmin, factor VIII, chromogranin, or neuron-specific enolase. Of the two tumors studied ultrastructurally, one contained an admixture of smooth muscle cells and cells resembling Schwann cells, and the second was populated by homogeneous fusiform mesenchymal cells separated by homogeneous matrix. Gastrointestinal stromal tumors (GIST) have been recognized in humans, more recently in dogs and nonhuman primates, and now in equids. Most of these tumors are comprised of a loosely arranged network of spindled cells separated by myxoid matrix. GIST may be composed of myogenic, neurogenic, combined myogenic and neurogenic, and undifferentiated mesenchymal cells.

Gastrointestinal autonomic nerve (GAN) tumor is an uncommon specialized form of gastrointestinal stromal tumor (GIST). We report the case of a 46-year-old man affected by this tumor. The neoplasm arose from the sigmoid colon. The patient underwent surgery but eight months later an omental relapse occurred. A second laparotomy was successfully performed and the patient is free of disease at 21 months of follow-up. To our knowledge this is the first case of a large bowel GAN tumor described in the literature.

A case of malignant gastrointestinal stromal tumor (GIST) is reported. Histologically, spindle cell proliferation with remarkable whorl formations was predominant in the tumor. Immunohistochemically, the tumor cells were diffusely positive for CD117 (c-Kit) and vimentin and partially positive for CD34. Ultrastructurally, the desmosome-like structures and interdigitations occurred much more frequently in the areas with whorl formations. These organelles were considered to be closely associated with the whorl formations. Various kinds of cellular arrangements are revealed in GISTs, but remarkable whorl formations, such as in our case, are a rare variant pattern. Herein, we discuss the histopathologic differences between this and other tumors showing whorl formations and describe the meaning of this unique arrangement. GISTs are thought to be immature tumors, and, therefore, variations in histopathologic findings are recognized. Finally, the ultrastructural study of GISTs is useful for understanding the mechanisms forming whorl formations and the differentiation or pathogenesis of GISTs.

Regarding the size of endocrine granules in endocrine neoplasms including carcinoids, most authors have reported only the range of granule diameters, and few studies on detailed morphometry of granule sizes have been documented. The statistically comparative study of endocrine granule sizes among such neoplasms, therefore, presented many difficulties. In the present study, we investigated more detailed findings on the endocrine granule sizes by using statistical analyses of diameters of numerous (n > 200 from each tumor) endocrine granules measured randomly throughout the cytoplasm in 18 gastrointestinal carcinoids. The measured data were analyzed statistically to obtain the histogram, distribution curve, mean value, and standard deviation of granule diameters in each carcinoid. It was disclosed by the analyses that all rectal carcinoids possessed uniformly small endocrine granules in contrast to gastric and duodenal carcinoids, which showed wide distribution of granule sizes, having significantly greater diameters than those in the rectal carcinoid series. The correlation between endocrine granule sizes and producing hormone(s) was, however, not confirmed.

The level of expression and the phosphorylation status of the alpha subunit of initiation factor 2 (eIF2alpha) protein have been determined by comparing samples from human stomach, colon and sigma-rectum carcinomas with normal tissue from the same patients. The unphosphorylated and phosphorylated levels of cytoplasmic eIF2alpha, as well as the percentage of phosphorylated factor over the total, were significantly higher in stomach, colon and sigma-rectum tumours compared with normal tissue. The expression of this factor was also studied by using immunocytochemical methods, where redistribution towards the nucleus in tumour cells as compared with normal tissue was observed. Our results support a likely implication of eIF2alpha in gastrointestinal cancer.

We describe two cases of gastrointestinal stromal tumours with prominent oncocytic features. Both had features consistent with differentiation towards the interstitial cells of Cajal (CC). They were composed of nests and bundles of cells with abundant, deeply granular, eosinophilic cytoplasm. Immunohistochemical investigations revealed positivity with c-kit, vimentin and CD34 antibodies in both neoplasms. Ultrastructurally the neoplastic cells showed characteristic features of CC; they had synapse-like structures and dense core cytoplasmic granules. Oncocytic features were confirmed by immunohistochemistry using anti-mitochondrion antibody in both cases and by electron microscopy in one case (case 1). Although the CC are frequently described as mitochondrion-rich cells, oncocytic changes have not previously been reported as a feature of gastrointestinal autonomic nerve tumour (GANT)-like stromal tumours.

In the field of gut endocrinomas (carcinoids and relevant neoplasms), several classifications have been internationally accepted and utilized at varying frequency. The basis of the concepts regarding gut endocrinomas from which these classifications have been proposed were drawn from the different aspects. These included embryology, histologic growth patterns, histochemistry including silver impregnations, electron microscopic morphology of endocrine secretory granules, endocrine cell types and histologic morphology along with functional characteristics, supplemented by immunohistochemical features. Due to continuous progress being made in this particular field of research and the many new discoveries made by pioneering investigators, the concepts of gut endocrinomas have been modified and revised during such long history of the research activities. This study aims to re-evaluate these classifications in relation to the concepts of gut endocrinomas, and to select and supply rearranged classifications that may be easily utilized for practical purposes. This study also proposes a comprehensive overview of histogenesis in the gut endocrinoma group. This consists of typical carcinoids and their atypical variants taken in relation to the carcinomatous group including ordinary carcinomas and their variants with endocrine elements. Special emphasis is given to the point that there is a gradual transition, one without a definite boundary between these tumors.

Cells having a signet ring appearance can occur in mesenchymal, lymphoid, and other nonepithelial neoplasms. We report the case of an intestinal stromal tumor with smooth muscle differentiation and a prominent signet ring cell component. The presence of signet ring forms of smooth muscle cells in sections of paraffin-embedded tissue often contrasts with a lack of cytoplasmic spaces by electron microscopy, and the ultrastructural finding of signet ring-like areas in the present case can be attributed to the fact that the tissue for electron microscopy was retrieved from paraffin blocks where this peculiar artifact already existed. Ultrastructural examination of the signet ring-like areas suggests that they originated as retraction spaces which may have resulted from variations in intracellular tension forces related to the distribution of actin filaments.

Gastrointestinal adenocarcinoma-derived cell lines were studied in order to determine their pattern of expression of basement membrane components and their ability to form a basement membrane. In contrast to the well-preserved expression of laminin beta 2, beta 3, gamma 1, and gamma 2 chain mRNAs, five of eight gastrointestinal cancer cells lacked alpha 3 mRNA. Immunohistochemical and electron microscopic examination of four cell lines transplanted subcutaneously to SCID mice demonstrated the presence of both alpha 3 and alpha 5 chains and the formation of a basal lamina in two cases. The other two cell lines lacked both alpha 3 and alpha 5 chains and could not form a basal lamina, suggesting that this deficiency may be a factor which affects their ability to form a basement membrane. This abnormality might play some role in stromal invasion by tumour cells in gastrointestinal cancer.

The term amphicrine refers to cells, and tumors, which show both exocrine and endocrine features. Author s aim was to analyse the characteristics of these neoplasms. 40 suspicious cases were reviewed. Mucin-stains (PAS, diastase-PAS, Stains-all, Alcian-blue), immunohistochemistry (antibodies against Neuron-Specific Enolase (NSE), and Chromogranin A (CGA), and electronmicroscopic studies were performed to demonstrate exocrine and/or endocrine features of the tumor cells. By means of these methods, 16 cases turned out to be amphicrine tumors. Among them, there were 4 sinonasal, 1 bronchial, 1 mediastinal, 8 gastrointestinal and 2 suprarenal gland neoplasms. In connection to the subject, a brief review is given of amphicrine tumor, regarding its etiological and pathological aspects. These tumors form a distinct clinicopathological entity and should be separated from both neuroendocrine tumors and adenocarcinomas.

The current significant role of transmission electron microscopy in the evaluation of soft tissue tumors when correlated with conventional histological and immunohistochemical studies is discussed for the following entities: myxofibrosarcoma, storiform-pleomorphic fibrosarcoma (malignant fibrous histiocytoma), and myofibrosarcoma; dermatofibrosarcoma protuberans; hemangiopericytoma; monophasic synovial sarcoma; extrarenal rhabdoid tumor; soft tissue perineurioma; and gastrointestinal stromal tumors, notably the so-called autonomic nerve variant.

Neuroendocrine tumors may derive either from neuroectoderm or endoderm. Both may present with a similar histologic pattern known as "Zellballen" regardless of their histogenetic origin, making it difficult to separate the two different histogenetic entities in certain cases. To evaluate the usefulness of sustentacular cells in the recognition of tumors of paraganglionic origin, the authors analyzed immunohistochemical and ultrastructural characteristics of 25 paragangliomas and 19 pulmonary and 10 small intestinal carcinoids. Sustentacular cells with characteristic dendritic features, strong immunoreactivity for S-100 protein, and agranular cytoplasm by electron microscopy were found consistently in the paragangliomas and not found in typical carcinoid tumors, except for four examples of spindle cell carcinoid of the lung. The presence of sustentacular cells in tumors with "Zellballen" pattern therefore denotes paraganglionic origin.

The gastrointestinal autonomic nerve (GAN) tumor, or plexosarcoma, is a very uncommon stromal tumor of the gastrointestinal tract and retroperitoneum. Distinction of GAN tumors from other stromal tumors is not possible based on imaging studies, and needs specific ultrastructural and inmunohistochemical techniques. There are some morphologic characteristics that the radiologist should know, so as to include these rare tumors in the differential diagnosis of an abdominal mass. We report two new cases: small bowel (jejunum-ileum) and stomach GAN tumors.

Seven of 15 gastrointestinal stromal tumors from the author's file were classified as plexosarcomas when examined by electron microscopy and immunohistochemistry. Electron microscopy was essential for the diagnosis.

Sections from 35 formalin-fixed, paraffin-embedded, canine gastrointestinal stromal tumors consisting of 14 leiomyomas (five stomach, three small intestine, two colon, four rectum), 18 leiomyosarcomas (one stomach, five small intestine, nine cecum, three rectum), two undifferentiated sarcomas (two stomach), and one neurofibrosarcoma (small intestine) were examined for the expression of vimentin, S-100 protein, alpha-smooth muscle actin, and desmin via immunoperoxidase methodology using an avidin-biotin complex technique. The leiomyomas were 4/14 (29%) vimentin-positive, 3/14 (21%) S-100 protein-positive, 10/14 (71%) alpha-smooth muscle actin-positive and 13/14 (93%) desmin-positive. Leiomyosarcomas were 18/18 (100%) vimentin-positive, 11/18 (61%) S-100 protein-positive, 9/18 (50%) a-smooth muscle actin-positive, and 15/18 (83%) desmin-positive. The undifferentiated sarcomas were 2/2 (100%) vimentin-positive, 2/2 (100%) S-100 protein-positive, 1/2 (50%) alpha-smooth muscle actin-positive, and 0/2 (0%) desmin-positive. The neurofibrosarcoma was vimentin and S-100 protein-positive and alpha-smooth muscle actin- and desmin-negative. Thirty-one of thirty-five (89%) of all neoplasms demonstrated reactivity for either desmin and/or alpha-smooth muscle actin. S-100 protein reactivity occurred in 17/35 (49%) of all specimens. Lack of desmin and alpha-smooth muscle actin reactivity occurred in 4/35 (11%) of all specimens, all of which were vimentin-positive. The immunohistochemical results indicate that the majority of canine gastrointestinal stromal tumors (GIST) with light microscopic features of smooth muscle cells have immunohistochemical staining patterns supporting smooth muscle differentiation. Vimentin reactivity correlated with a light microscopic diagnosis of malignancy. The lack of smooth muscle cell markers in some tumors and the high percentage of cases positive for S-100 protein may suggest a more complex histogenesis or differentiation for subgroups of these tumors.

The gastrointestinal autonomic nerve tumor (GAN tumor) is an uncommon stromal tumor with a morphological feature resembling the cell processes of the enteric plexus, and was originally termed a plexoma or plexosarcoma. Light microscopic studies show the GAN tumor most often consists of spindle-shaped cells indistinguishable from a smooth muscle tumor or Schwann cell tumor. Immunohistochemical and ultrastructural examinations of 18 cases of gastrointestinal stromal tumor (GIST) were performed. During ultrastructural examination, all of the 12 cases which were immunohistochemically positive for S-100 protein or neuron-specific enolase (NSE) showed synapse-like structures containing dense core neurosecretory granules measuring 100-200 nm, and 40-60 nm endocytoplasmic vesicles. These results suggest that most GIST of neurogenic origin are tumors derived from the myenteric nerve plexus.

We found intracytoplasmic crystalloids in two of six cases (33.3%) of gastrointestinal (GI) schwannomas. The crystalloid inclusions were periodic acid-Schiff (PAS) positive with diastase-resistance and stained blue with Masson's trichrome. They were needle-shaped and about 1 to 15 microm in length at microscopic levels. They had varying electron density revealed by electron microscopy and some of them showed distinct lattice structure with periodicity of about 9 nm. Survey of soft tissue schwannomas (n = 20) and S-100-negative GI stromal tumors (n = 41) did not detect such crystalloids. Although the origin and differentiation of GI stromal tumors (GISTs) have been a source of controversy, these intracytoplasmic crystalloids may be a marker for Schwann cell differentiation in some GIST.

Gastrointestinal autonomic nerve tumor (GANT) is a specialized form of stromal neoplasm whose ultrastructural features support a myenteric plexus derivation and provide the basis for its diagnosis. GANT actual frequency, relationship to skeinoid fibers, and CD34 expression status are some of the controversial aspects of this entity. Out of 14 gastrointestinal stromal tumors gathered during a 1-year period, six (42%) instances were diagnosed as GANT by electron microscopic study of at least five ultrathin sections per case. Additionally, GANTs were immunohistochemically investigated with a panel of nine antibodies including CD34. Ultrastructurally, every GANT case showed diagnostic findings and evidence of skeinoid fibers, whereas immunohistochemically all except one were CD34 positive. Immunoreactivity for neuron-specific enolase, synaptophysin, and vimentin was a common occurrence as well. In conclusion, GANT seems to be more frequent than hitherto recognized, skenoid fibers are a regular feature of GANT, and a positive CD34 immunoreaction does not discriminate between GANT and other non-smooth muscle, non-schwannian neoplasms.

Recent data suggest that functional receptors (R) for vasoactive intestinal peptide (VIP) are expressed on various tumor cells. The high-level expression of VIPR on tumor cells provided the basis for the successful use of 123I-labeled VIP for the in vivo localization of intestinal adenocarcinomas and endocrine tumors. We here report an update of our imaging results using 123I-VIP (150-200 MBg/1 microgram/patient) in 169 patients. In patients with pancreatic adenocarcinomas without liver metastases, the primary/recurrent tumor was visualized in 16 of 18 patients (89%) and liver metastases were imaged in 15 of 16 patients. In 11 of 12 patients with colorectal adenocarcinomas, the primary/recurrent tumor (92%) was imaged by 123I-VIP. Also, in 21 of 25 patients, liver metastases (84%); in 3 of 6 patients, lung metastases (50%); and in 4 of 5 patients, lymph-node metastases (80%) were imaged by 123I-VIP. In 10 of 10 patients with gastric adenocarcinomas, the primary/recurrent tumor; in 3 of 4 patients, liver metastases; and in 2 of 2 patients, lymph-node metastases were visualized by 123I-VIP. 123I-VIP localized primary intestinal carcinoid tumors in 15 of 17 patients (88%) and 8 of 10 primary insulinomas (80%). We conclude that the 123I-VIPR scintigraphy localizes intestinal adenocarcinomas and endocrine tumors as well as metastatic tumor sites.

Fifty-six gastrointestinal stromal tumors (GIST) were subclassified by ultrastructural examination and by immunophenotypic analysis using a panel of 13 antibodies. Eighty percent of the tumors originated in the stomach and small intestines. The neoplasms were classified as follows: 42.9% smooth muscle tumors (4 leiomyomas, 9 spindle cell and 8 epithelioid leiomyosarcomas, and 3 mixed spindle cell and epithelioid leiomyosarcomas); 37.5% gastrointestinal autonomic nerve tumors (GANT), 47.6% of which arose in the small intestines; 8.9% mixed leiomyosarcoma/neurogenic tumors; and 10.7% undifferentiated GIST, not otherwise specified. The muscle common actin antibody HHF-35, variably reactive with tumor cells composing 23 of 24 smooth muscle tumors, was found to be the most sensitive marker of leiomyocyte differentiation. One immunophenotypically questionable spindle cell leiomyosarcoma was diagnosed by electron microscopy. Since neuron specific enolase positive cells were found in 1/3 of the leiomyosarcoma cases, the ultrastructural demonstration of synapse-like structures and neurosecretory granules was required for diagnosing GANTs. The immunophenotype of the ultrastructurally undifferentiated GIST was vimentin and CD34+. Variable numbers of ultrastructurally undifferentiated cells also we found in all of the tumors except 2 leiomyomas. CD34 was also expressed in smooth muscle (54%) and GAN (62%) tumors. Despite their similar light microscopic appearance, GIST are phenotypically heterogeneous, requiring both ultrastructural and immunohistochemical studies for accurate characterization.

The present report describes a case of a 27 year old patient with epigastric pain of moderate intensity, accompanied by hiporexia, weight loss and melena who was hospitalized in August 1.994 after 17 days of these signs and symptoms. Colonoscopy revelead a 6 cms polypoid, ulcerated lesion in the hepatic angle of the colon. At surgery, a 5 x 5 cms tumoral lesional 1.5 cms from the Treitz adhered to the small bowel was found. The gross findings of the specimen revealed an exophitic ulcerated tumor that measured 10 x 10 x 9 cms. Satellite nodules up to 2 cms in diameter were seen in contact with the large bowel mucosae. Light microscopy, immunohistochemical and ultrastructural studies, indicated a diagnosis of PLEXOSARCOMA.

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.

Previous reports revealed a discrepancy in gelatinase A localization in human cancers; i.e., protein localization in cancer cells and mRNA localization in stromal fibroblastic cells. To clarify this, we conducted immunoelectron microscopic study of gelatinase A in cancer and stromal cells in human gastrointestinal and skin carcinomas. Although both carcinoma cells and fibroblasts were positive for gelatinase A, the subcellular localizations were different. On immunoelectron microscopy, fibroblasts showed immunoreactivity in the lumen of the rough endoplasmic reticulum (rER) or in the cytosol on the surface of rER, demonstrating synthesis of the protein. Carcinoma cells showed diffuse deposition of gelatinase A in the cytosol, suggesting the accumulation of the antigen both in adenocarcinoma and squamous cell carcinoma. Immunoreactivity along the cell membrane was demonstrated in one case of skin carcinoma. Macrophages showed also diffuse deposition of gelatinase A in the cytosol. In conclusion, we found a qualitative difference of gelatinase A localization between carcinoma cells and fibroblasts, and concluded that carcinoma cells may not be important in the secretion of gelatinase A.

A gastrointestinal stromal tumor, arising from the rectal ampulla of a 63-yr-old man, was investigated using conventional techniques as well as Western blot analysis of its cytoskeleton proteins. The expression of desmin, muscle-specific actins, vimentin, S-100 protein, chromogranin, neuron-specific enolase, and keratins was studied using the avidin-biotin technique. The tumor cells showed a positive reaction only to antivimentin antibody. Ultrastructural analysis failed to provide conclusive evidence for neural or muscular origin of the tumor. Western blot analysis of the tumor whole-protein extract allowed identification of the presence of gamma-smooth-muscle actin, thus suggesting an enteric smooth-muscle origin of the tumor. This result seems partially to support a parenchymal smooth-muscle origin for S-100 protein and desmin-negative gastrointestinal tumors.

Nine cases are presented of a distinctive morphologic variant of myogenic gastrointestinal stromal tumor characterized by an unusually prominent myxoid stromal background reminiscent of a neural neoplasm but lacking the immunohistochemical or ultrastructural features of peripheral nerve sheath or ganglionic differentiation. The patients included six women and three men aged 42 to 86 years (mean, 70). The lesions occurred in the stomach (seven cases) and small intestine (two cases) and ranged in size from 2.5 to 9.5 cm. They were described grossly as well circumscribed, unencapsulated, with a prominently myxoid and often cystic cut surface. Histologically, the lesions were composed of a proliferation of round, spindle, or stellate cells embedded in an abundant myxoid stroma. Histochemical stains showed strong positive reaction of the myxoid stromal background with alcian blue at pH 2.5; this staining reaction was abolished by treatment with hyaluronidase, indicating an abundance of connective tissue mucosubstances rich in hyaluronic acid. Immunohistochemical stains showed strong positivity of the tumor cells with vimentin antibodies in all cases and focal weak to moderate positive staining with muscle actin (HHF35) in eight cases and with desmin in two. Stains for keratin, S-100; epithelial membrane antigen, and collagen type IV were uniformly negative. Ultrastructural examination carried out in all cases showed features consistent with those previously described for myogenic gastrointestinal stromal tumors, namely, scattered mitochondria and prominent Golgi apparati, strands of rough endoplasmic reticulum, focal accumulation of intracytoplasmic microfilaments with occasional focal condensations, subplasmalemmal attachment plaques and immature cell junctions, focal extracellular basal lamina material, and surface-oriented micropinocytotic activity. The myxoid changes observed in these tumors may represent a secondary, nonspecific reaction pattern of the tumor cells to some noxious stimulus, or they may be a form of degenerative phenomenon such as that commonly observed in smooth-muscle tumors of the uterus and other sites. Myogenic gastrointestinal stromal tumors with prominent myxoid stroma should be distinguished from benign schwannoma of the stomach and gastrointestinal autonomic nerve tumors. Because of the differences in prognosis for these entities, immunohistochemical and ultrastructural examinations are recommended for the evaluation of gastrointestinal stromal neoplasms with prominent myxoid features.

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.

DNA ploidy was investigated by flow cytometry (FC) and image analysis (IA) in paraffin-embedded tissue sections from 36 stromal tumors of the gastrointestinal tract. The results of both techniques were correlated with pathologic features of the tumors and survival. Ten (27.8%) tumors were aneuploid by FC and IA. Most of the diploid tumors were identified by both techniques, but FC appeared to be superior to tissue section IA for identification of aneuploid tumors (25% vs. 13.8%). Aneuploidy by FC correlated with pathologic grade and mitotic index (P < .05), and a trend to short survival was also detected (P < .1). No similar correlation was found by IA. Enlargement and variation of nuclei may explain the discrepancy between FC and IA.

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)