Glucagon cell adenomatosis: a newly recognized disease of the endocrine pancreas.

BACKGROUND: Glucagon-producing tumors are either solitary neoplasms of the pancreas, occasionally associated with a glucagonoma syndrome, or multiple neoplasms associated with multiple endocrine neoplasia type 1 (MEN1). We observed a previously undescribed multicentric glucagon-producing tumor disease that is not related to MEN1. METHODS: Pancreatic tissue from four patients showing multiple neuroendocrine microadenomas and in two cases also macrotumors were screened for hormones using immunohistochemical and morphometric methods. MEN1, von Hippel-Lindau, and p27 germ line and somatic mutation analysis was performed. Deletion of MEN1 (11q13), von Hippel-Lindau (3p25), and the centromere 11 and 3 gene locus was determined by fluorescence in situ hybridization. DNA copy number changes were studied using array comparative genomic hybridization. RESULTS: The pancreatic tissue from the four patients contained more than 870 microadenomas and 10 macrotumors, all of which expressed exclusively glucagon and none of which showed evidence of malignancy. In addition, many islets were unusually large and showed glucagon cell hyperplasia. There was no clinical or molecular evidence of any hereditary tumor disease, and changes in the MEN1 gene were only seen in individual tumors. Array comparative genomic hybridization of one macrotumor and 20 pooled microadenomas revealed a homogeneous diploid chromosome set. CONCLUSIONS: The findings are sufficiently distinctive to suggest a new neoplastic disease of the endocrine pancreas that we recommend calling glucagon cell adenomatosis. Clinically, this disease may be an incidental finding, or it may lead to a glucagonoma syndrome.

Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia.

BACKGROUND: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence. METHODS: Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded. RESULTS: Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas. CONCLUSIONS: Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.

Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity.

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.

Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases.

BACKGROUND: Tracing the origin of a metastasis of a neuroendocrine carcinoma is a challenge. The transcription factors Cdx2 and TTF1 have been found to be helpful in identifying well-differentiated neuroendocrine tumors of gastrointestinal and pulmonary origin, respectively. So far, such a marker is lacking for pancreatic neuroendocrine tumors (PETs) and metastases thereof. Islet1 (Isl1) is a transcription factor expressed in pancreatic islet cells. The aim of this study was (1) to test the specificity and sensitivity of Isl1 as a marker of PETs, and (2) to test the specificity and sensitivity of a panel of markers, including Isl1, Cdx2, and TTF1, for the localization of the primary. DESIGN: One hundred eighty-eight primary gastroenteropancreatic and pulmonary endocrine tumors and 49 metastases thereof were examined. Immunohistochemistry using antibodies directed against Isl1, Cdx2, and TTF1 was performed and the staining results were scored semiquantitatively. RESULTS: Isl1 proved to be a highly specific marker for pancreatic endocrine tumors. In 84 primary PET its specificity was 78.4% (sensitivity 74.3%) and in 18 metastases of PET the specificity reached 100% (sensitivity 77.8%). Strong Cdx2 staining showed a specificity for gastrointestinal origin of 83.9% (sensitivity 82%) in primary tumors and of 100% (sensitivity 40%) in metastases. Including weakly positive tumors lead to a decreased specificity but an increased sensitivity. TTF1 expression was detected in 2 PET and 1 ileal primary tumor only and was absent in all metastases of gastroenteropancreatic endocrine tumors. CONCLUSIONS: Isl1 is a reliable marker of pancreatic endocrine tumors and metastases thereof. It shows a comparable sensitivity and specificity as Cdx2 as a marker of ileal and appendiceal neuroendocrine tumors and their metastases. TTF1 is very rarely expressed in well-differentiated gastroentero-PETs. Therefore, the panel of Isl1, Cdx2, and TTF1 seems useful for examining metastases of well-differentiated endocrine carcinomas of unknown origin.

Differentiation of human follicular thyroid adenomas from carcinomas by gene expression profiling.

It is difficult to distinguish benign from malignant follicular thyroid tumors by histological or cytological examination. The goal of this study was to reveal gene expression variations between benign and malignant follicular lesions of the thyroid gland. We investigated gene expression profiles from 24 follicular thyroid tumors (12 carcinomas and 12 adenomas) and 13 normal thyroid tissues using high-density human cDNA arrays. The identification of gene expression changes was based on signal intensity ratios of tumor versus normal thyroid parenchyma. Expression patterns of a set of known genes were found to be significantly different between follicular adenomas and follicular carcinomas. Our results demonstrate a potential use of gene expression profiling for differentiating benign from malignant follicular thyroid tumors. A detailed investigation of the differentially expressed genes could give new insights into molecular pathways of malignant transformation of thyroid follicular neoplasm and may help to develop a molecular tool for the preoperative differential diagnosis.

WHO 2004 criteria and CK19 are reliable prognostic markers in pancreatic endocrine tumors.

BACKGROUND: It is difficult to predict the biologic behavior of pancreatic endocrine tumors in absence of metastases or invasion into adjacent organs. The World Health Organization (WHO) has proposed in 2004 size, angioinvasion, mitotic activity, and MIB1 proliferation index as prognostic criteria. Our aim was to test retrospectively the predictive value of these 2004 WHO criteria and of CK19, CD99, COX2, and p27 immunohistochemistry in a large series of patients with long-term follow-up. DESIGN: The histology of 216 pancreatic endocrine tumor specimens was reviewed and the tumors were reclassified according to the 2004 WHO classification. The prognostic value of the WHO classification and the histopathologic criteria necrosis and nodular fibrosis was tested in 113 patients. A tissue microarray was constructed for immunohistochemical staining. The staining results were scored quantitatively for MIB1 and semiquantitatively for CK19, COX2, p27, and CD99. The prognostic value of these markers was tested in 93 patients. RESULTS: The stratification of the patients into 4 risk groups according to the 2004 WHO classification was reliable with regard to both time span to relapse and tumor-specific death. In a multivariate analysis, the CK19 status was shown to be independent of the WHO criteria. By contrast, the prognostic significance of COX2, p27, and CD99 could not be confirmed. CONCLUSIONS: The 2004 WHO classification with 4 risk groups is very reliable for predicting both disease-free survival and the time span until tumor-specific death. CK19 staining is a potential additional prognostic marker independent from the WHO criteria for pancreatic endocrine tumors.

Hereditary neuroendocrine tumors of the gastroenteropancreatic system.

Approximately 5-10% of neuroendocrine tumors (NETs) of the gastroenteropancreatic system (GEP) have a hereditary background. The known inherited syndromes include multiple endocrine neoplasia type 1, neurofibromatosis type 1, von Hippel-Lindau disease, and the tuberous sclerosis complex. This review discusses for each of these syndromes the: (1) involved genes and specific types of mutations, (2) disease prevalence and penetrance, (3) affected neuroendocrine tissues and related clinical syndromes, (4) special morphological features of NETs and their putative precursor lesions. In addition, GEP-NETs clustering in individual families or associated with other malignancies without known genetic background are discussed.

Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas.

CONTEXT: The occurrence of multiple small pancreatic endocrine tumors in patients suffering from multiple endocrine neoplasia type 1 (MEN1) represents a unique possibility to study early neoplasms and their potential precursor lesions. To date, it is unknown whether small islet-like endocrine cell clusters found in MEN1 patients are neoplastic or rather hyperplastic. It is also unclear whether microadenomas develop from islets. DESIGN: We hypothesized that monohormonal endocrine cell clusters observed in MEN1 patients are small neoplasms with loss of heterozygosity of the MEN1 locus. Using a technique combining fluorescence in situ hybridization of the MEN1 locus and the centromeric region of chromosome 11q with hormone immunostaining, we examined resection specimens from four MEN1 patients. We focused our investigations on the following: 1) typical microadenomas; 2) monohormonal endocrine cell clusters; 3) endocrine and exocrine structures entrapped in microadenomas; and 4) morphologically normal islets. RESULTS: Loss of one MEN1 allele was found in all 27 microadenomas and 19 of 20 (95%) monohormonal endocrine cell clusters. By contrast, it was absent in islets and ductal or acinar structures. Our results indicate that monohormonal endocrine cell clusters represent a minute form of microadenomas. CONCLUSION: The frequent presence of single nonneoplastic insulin cells in microadenomas and the occurrence of microadenomas in islets suggest an islet origin of microadenomas. Islet hyperplasia does not seem to be an obligatory stage in pancreatic MEN1-associated tumor development.

Molecular characterization of well-differentiated human thyroid carcinomas by cDNA arrays.

Well-differentiated papillary and follicular thyroid carcinomas are the two most common types of thyroid cancer. Although cancerous cells in both types phenotypically resemble the epithelial follicular cell, the tumors display different histological characteristics and clinical outcomes. Molecular defects contributing to the separate development pathways remain largely unclear. We evaluated gene expression profiles to generate a detailed molecular characterization of the two tumor types, attempting to detect novel diagnostic and clinical markers. Gene expression profiling of 46 thyroid samples (16 papillary carcinomas, 13 follicular carcinomas and 17 normal thyroid specimens) was performed by using high-density human UniGene cDNA arrays. The identification of differentially expressed genes was based on a comparison of signal intensity ratios of tumor versus normal tissues. A cross-validation of individual filter-array hybridizations and real-time PCR analysis of selected genes were carried out to confirm data reproducibility and reliability. The majority of genes with altered expression were found in both papillary and follicular carcinomas, reflecting a close relationship between the two tumor types. However, 123 genes consisting of 45 known and 78 unknown genes were shown to be differentially expressed between papillary and follicular carcinomas. Follicular variants of papillary carcinoma, clustered together with classical papillary carcinoma, could be differentiated from follicular carcinoma. Our study revealed a set of genes differentiating follicular carcinoma from classical papillary carcinoma and follicular variant. The data generated in this study could serve as a useful source for further investigation of pathways of papillary and follicular differentiation of thyroid cancer.

Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features.

Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

Three-dimensional architecture of the left ventricular myocardium.

Concepts for ventricular function tend to assume that the majority of the myocardial cells are aligned with their long axes parallel to the epicardial ventricular surface. We aimed to validate the existence of aggregates of myocardial cells orientated with their long axis intruding obliquely between the ventricular epicardial and endocardial surfaces and to quantitate their amount and angulation. To compensate for the changing angle of the long axis of the myocytes relative to the equatorial plane of the ventricles with varying depths within the ventricular walls, the so-called helical angle, we used pairs of cylindrical knives of different diameters to punch semicircular slices from the left ventricular wall of pigs, the slices extending from the epicardium to the endocardium. The slices were pinned flat, fixed in formaldehyde, embedded in paraffin, sectioned, stained with azan or hematoxilin and eosin, and analyzed by a new semiautomatic procedure. We made use of new techniques in informatics to determine the number and angulation of the aggregates of myocardial cells cut in their long axis. The alignment of the myocytes cut longitudinally varied markedly between the epicardium and the endocardium. Populations of myocytes, arranged in strands, diverge by varying angles from the epicardial surface. When paired knives of decreasing diameter were used to cut the slices, the inclination of the diagonal created by the arrays increases, while the lengths of the array of cells cut axially decreases. The visualization of the size, shape, and alignment of the myocytic arrays at any side of the ventricular wall is determined by the radius of the knives used, the range of helical angles subtended by the alignment of the myocytes throughout the thickness of the wall, and their angulation relative to the epicardial surface. Far from the majority of the ventricular myocytes being aligned at angles more or less tangential to the epicardial lining, we found that three-fifths of the myocardial cells had their long axes diverging at angles between 7.5 and 37.5 degrees from an alignment parallel to the epicardium. This arrangement, with the individual myocytes supported by connective tissue, might control the cyclic rearrangement of the myocardial fibers. This could serve as an important control of both ventricular mural thickening and intracavitary shape.

Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome.

It has been suggested that microadenomatosis of the endocrine pancreas is a hallmark of the multiple endocrine neoplasia type 1 syndrome (MEN1). This study attempts to elucidate the relationship between pancreatic microadenomatosis and the MEN1 and von Hippel-Lindau (VHL) syndromes. Pancreatic tissue specimens from 37 patients (with either microadenomatosis or the MEN1 syndrome) were analyzed using immunohistochemistry, confocal laser scanning microscopy, and morphometric methods. The MEN1 and the VHL status were assessed on the basis of clinical criteria (all patients) and PCR-based mutational analysis (15 and 5 patients, respectively). Pancreatic microadenomatosis was found in 35 of 37 patients, 28 of whom fulfilled the clinicopathologic criteria and 13 the genetic criteria for MEN1, whereas none of the patients had evidence of a VHL syndrome. Microadenomas were present in 26 of the 28 MEN1 patients, and all these tumors were consistently multihormonal. Five of the 9 patients with microadenomatosis and no clinical evidence for MEN1 or VHL also lacked mutations for the respective genes. Five of these 9 patients suffered from hyperinsulinism and revealed multiple insulin-positive tumors. The other patients were nonsymptomatic and showed multiple glucagon-expressing neoplasms. In microadenomatosis patients with and without the MEN1 syndrome, a subset of morphologically normal-appearing islets showed increased endocrine cell proliferation. In conclusion, endocrine multihormonal microadenomatosis of the pancreas is a feature of MEN1. In addition, a monohormonal type of pancreatic microadenomatosis was identified that consisted of either insulinomas or glucagon-producing tumors and was not associated with MEN1 or VHL.

Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas.

BACKGROUND & AIMS: The identification of precursor lesions has a great impact on the understanding of tumorigenesis. Precursor lesions of endocrine tumors are known to occur in the setting of the MEN1 syndrome. The aim of this study was to test the hypothesis that MEN1-associated duodenal gastrinomas originate from diffuse preneoplastic gastrin cell changes. Precursor lesions may precede the development of duodenal gastrinomas because, in contrast to sporadic gastrinomas, these tumors are usually multiple. METHODS: The distribution of endocrine cells in the nontumorous duodenal tissue was analyzed qualitatively and quantitatively for 25 patients operated on for a duodenal gastrinoma. MEN1 status was assessed clinically and by polymerase chain reaction-based mutational analysis. RESULTS: Fourteen of 25 patients with gastrinoma had proliferative, hyperplastic lesions consisting of gastrin cells in the nontumorous duodenal mucosa, similar to the gastric enterochromaffin-like cell lesions observed in chronic atrophic gastritis. All patients with Zollinger-Ellison syndrome with proven MEN1 had such proliferative gastrin cell lesions, and all patients with Zollinger-Ellison syndrome without precursor lesions were MEN1 negative. CONCLUSIONS: Duodenal gastrinomas in MEN1, but not sporadic duodenal gastrinomas, are associated with proliferative gastrin cell changes within the nontumorous mucosa. It is likely that these lesions precede the development of MEN1-associated duodenal gastrinomas.

Persistent hyperinsulinemic hypoglycemia in 15 adults with diffuse nesidioblastosis: diagnostic criteria, incidence, and characterization of beta-cell changes.

Persistent hyperinsulinemic hypoglycemia (PHH) in adults that is not caused by an insulinoma is a rare and not well-characterized disease that has been named nesidioblastosis. In this study, we defined and scrutinized criteria for its histologic diagnosis, assessed its relative incidence, and discussed its pathogenesis. In pancreatic specimens from 15 adult patients with PHH in whom no insulinoma was detected and in 18 adult control patients, the endocrine tissue was screened for islet and beta-cell changes. The diagnostic reliability of the findings was checked by an interobserver analysis. The relative frequency of the disease was assessed in a series of 232 patients with PHH. Finally, genetic analysis of the menin gene was performed. Among the various indicators of islet changes, beta-cell hypertrophy characterized by enlarged and hyperchromatic beta-cell nuclei was the most significant and diagnostic finding in patients with PHH. The interobserver analysis revealed 100% specificity and 87.7% sensitivity. The hyperfunctional state of the beta-cells was not associated with changes in the subcellular distribution of insulin and proinsulin, proliferative activity, or mutations of the menin gene. Our results indicate that diffuse nesidioblastosis in adult patients with PHH resembles that seen in neonates suffering from PHH. The most important criterion for the diagnosis is the beta-cell hypertrophy. As approximately 4% of adult patients with PHH are affected by diffuse nesidioblastosis, this disease is not as rare as it has been thought to be. Pathogenetically, the defective insulin secretion could be based on a molecular defect.

Absence of BRAF gene mutations differentiates spitz nevi from malignant melanoma.

BACKGROUND: Distinction of Spitz nevus from malignant melanoma is sometimes difficult on the basis of conventional histology. A high rate of BRAF gene mutations in malignant melanomas (66%) and nevi (82%) has recently been reported. MATERIALS AND METHODS: We screened a series of 20 Spitz nevi for BRAF mutations in exons 11 and 15 by denaturing gradient gel electrophoresis (DGGE). RESULTS: BRAF mutations could not be identified in Spitz nevi. CONCLUSION: Our results show that mutations within the BRAF gene are useful markers for the differential diagnosis between Spitz nevus and malignant melanoma.

The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification.

Although well established in medical terminology, the term carcinoid is no longer adequate to cover the entire morphological and biological spectrum of neoplasms of the disseminated neuroendocrine cell system. Therefore, instead of carcinoid, the WHO classification published in 2000 uses the general terms neuroendocrine tumor and neuroendocrine carcinoma. In this review a classification of gastroenteropancreatic neuroendocrine tumors based on the WHO criteria is described. We also classify and comment on the most important tumor entities. On the basis of localization and of various morphological and biological criteria, we distinguish between benign neuroendocrine tumors, tumors with uncertain malignant potential, and tumors showing low-grade and high-grade malignancy.

Molecular genetics of gastroenteropancreatic endocrine tumors.

To elucidate the molecular background of sporadic gastroenteropancreatic endocrine tumors, several investigations into chromosomal alterations and allelic imbalances have identified several chromosomal regions of interest. These regions might harbor candidate genes important in tumor development and progression. However, only a small number of genes have been thoroughly analyzed, and only very few were shown to be altered in a substantial subset of tumors. Therefore, we are far from understanding the molecular mechanisms of tumor initiation and progression in gastroenteropancreatic endocrine tumors, although some "molecular patterns" are currently emerging. In this review, chromosomal alterations, that is, allelic losses and gene mutations, identified in gastroenteropancreatic endocrine tumors are briefly summarized. Molecular differences among various subtypes of gastroenteropancreatic endocrine tumors are highlighted in view of their role as indicators of separate genetic pathways.

CGH analysis shows genetic similarities and differences in atypical fibroxanthoma and undifferentiated high grade pleomorphic sarcoma.

BACKGROUND: Atypical fibroxanthoma (AFX) and undifferentiated high grade pleomorphic sarcoma (UpS) are histologically very similar, if not identical. However, they differ significantly in clinical outcome. MATERIALS AND METHODS: We used comparative genomic hybridization (CGH) to screen 24 AFX and 12 UpS for genomic alterations. RESULTS: DNA copy number changes were observed in 20/24 AFX and in all UpS. The most frequent alterations occurring with comparable frequency in both tumors were deletions on chromosomes 9p and 13q. We also detected statistically significant differences of genetic alterations between the two tumors concerning deletions on 1q, 3p, 5q, 11p, 11q, gains on 7q, 12q and high level gains on 5p and 11q. CONCLUSION: Despite their very similar histology, AFX and UpS show clear differences in their genetic alterations. This might contribute to the different biological behavior of the two tumors. On the other hand the similarities in genetic alterations on chromosomes 9p and 13q might suggest a common pathogenetic pathway.