EWS-FLI1 fusion type appears to be prognostically relevant in ES, independent of tumor site, stage, and size. Further studies are needed to clarify the biologic basis of this phenomenon.

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90 -95%) or ERG (5-10%).A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n ‫؍‬ 85), apoptosis by TUNEL assay (n ‫؍‬ 66), and IGF-1R expression by immunostaining with antibody 1H7 (n ‫؍‬ 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P ‫؍‬ 0.049) or categorical (P ‫؍‬ 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P ‫؍‬ 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P ‫؍‬ 0.01, Mann-Whitney test; P ‫؍‬ 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), represents a clinicopathological entity with a variable neural differentiation, usually appearing as a bone or soft tissue lesion in a child or young adult. The primary genetic event is chromosomal translocation resulting in fusion of the EWS gene with a member of the ETS family of transcription factors.1 The most frequent translocation partner of EWS is FLI1 (90 -95%), followed by ERG (5-10%). These fusion products function as oncogenic aberrant transcription factors.2 Detection of these fusions is considered to be specific for ES/PNET, and has become a valuable tool for the differential diagnosis of primitive small round cell tumors. 3,4 There is a considerable molecular genetic heterogeneity within ES/PNET. As mentioned above, either FLI1 or ERG can rearrange with EWS in these gene fusions. Furthermore, for either gene fusion, additional heterogeneity stems from the location of the genomic breakpoints of the translocati...

BACKGROUND Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripheral neuroectodermal tumor (ES/PNET). The primary genetic alteration in ES/PNET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly specific for these tumors, and molecular variation in the structure of the EWS‐FLI1 fusion gene also is of prognostic significance. In contrast, secondary genetic alterations, such as P53 alterations, are relatively uncommon in ES/PNET, and their prognostic impact has not been extensively studied. METHODS Prechemotherapy, paraffin embedded, nondecalcified, primary tumor material in a well‐characterized series of 55 patients with ES/PNET with defined EWS‐FLI1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techniques for cell cycle regulators and proliferative markers, such as P53, P21WAF1, and Ki‐67, as well as by the terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) technique for apoptosis. Nuclear P53 expression in > 20% of tumor cells was scored as aberrant overexpression. Histologic response to neoadjuvant chemotherapy was assessed. RESULTS Aberrant P53 expression (in > 20% of tumor cells) was present in 6 patients (11%) but showed no statistically significant correlation with disease stage, tumor size, proliferation rate (Ki‐67), apoptotic rate (TUNEL), or EWS‐FLI1 fusion type. By univariate analysis, the P53 > 20% group showed a significantly poorer overall survival among patients with localized disease (n = 43 patients) (P = 0.001) and in the entire study group (P = 0.01). In multivariate Cox analyses of overall survival, P53 > 20% was the strongest negative factor among prognostic factors available at the time of diagnosis (P = 0.001; relative risk [RR] = 9) and when chemotherapy response was included in the analysis (P53 > 20%: P = 0.01; RR = 10). CONCLUSIONS P53 alteration appears to define a small clinical subset of patients with ES/PNET with a markedly poor outcome. The current observations warrant a systematic prospective study with comprehensive P53 mutation analysis. [See related article on pages 793–9, this issue.] Cancer 2000;89:783–92. © 2000 American Cancer Society.

Malignant struma ovarii is a very rare tumor, consisting of a struma ovarii with malignant change. Only 17 examples with metastases have previously been reported. We present a case which involved both ovaries and produced multiple metastases. Microscopy and ultrastructure were identical to a mixed papillary and follicular carcinoma of the thyroid gland. Characteristic ultrastructural features of malignant struma ovarii are: microvilli on the surface and in the cytoplasmatic vacuoles; oncocytic transformation of cytoplasm of some cells; and presence of electron dense, granular and crystalline material (colloid) in the follicles and vacuoles. The patient's thyroid was normal. We conclude that malignant struma ovarii can only be diagnosed when a carcinoma arising in the thyroid gland can be excluded. Ultrastructure examination may provide useful diagnostic features separating malignant struma ovarii from strumal carcinoid and serous adenocarcinoma.

ABSTRACT— We studied liver changes in the hepatic biopsies of five patients with hyperthyroidism. A characteristic histopathologic picture consisting of mild to moderate intrahepatocytic cholestasis, lobular inflammatory infiltrate with some eosinophils, and Kupffer cell hyperplasia was found in all cases. We discuss the specificity, clinico‐pathological correlations and the possible pathophysiology of these lesions.

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We report a case of a 13-year-old girl with soft tissue sarcoma of the hand, which showed muscle and neuroectodermal immunophenotypes. Molecular studies were performed on RNA collected from fine-needle aspiration (FNA) cytology and peripheral blood samples by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis. This biphenotypic tumor showed simultaneous expression of EWS-FLI1 and PAX3-FKHR transcripts, specific of Ewing family tumors and alveolar rhabdomyosarcoma, respectively. Although childhood sarcomas with simultaneous muscle and neural differentiation have been described to have EWS-FLI1 transcripts, there are no reports of tumors with both transcripts. Cytological specimens are a good source of RNA for molecular studies. KEY WORDSMalignant ectomesenchymoma, Ewing sarcoma/PNET, alveolar rhabdomyosarcoma, EWS-FLI1 chimeric transcript, PAX3-FKHR chimeric transcript. ABBREVIATIONSRT-PCR, reverse transcription-polymerase chain reaction; FNA, fine-needle aspiration cytology; PNET, peripheral neuroectodermal tumor; MRI, magnetic resonance imaging; PBS, peripheral blood sample.

We have studied the clinical and morphological implications of renal siderosis, reviewing the autopsy protocols of 33 patients with valve prostheses in the heart. Seventeen patients had variable amounts of iron in the proximal tubules of the kidney. Renal siderosis was more frequent in women, in patients with longest time of evolution from the surgical procedure, and in patients with two valve prostheses. Histologically three degrees of renal siderosis may be defined: mild and moderate degrees of iron overload do not alter the kidney architecture, but kidneys, with severe siderosis show tubular atrophy and interstitial fibrosis. Episodes of acute renal failure (ARF) were more frequent in patients with more pronounced iron deposits, especially in the premortem stages. We conclude that renal siderosis may damage the proximal tubular epithelium of patients with valve prostheses in the heart; patients with renal overload of iron are more susceptible to episodes of ARF.