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Resumen El sarcoma de Ewing es un tumor oseo primitivo maligno que afecta sobre todo a ninos y adolescentes. Se caracteriza por masas densas de pequenas celulas redondas dispuestas en capas, sin diferenciacion histica. El sarcoma de Ewing forma parte de la familia de los tumores neuroectodermicos, que presentan una traslocacion 11–22 (o equivalente) caracteristica. Puede afectar a todos los huesos del esqueleto y, con menos frecuencia, desarrollarse de forma exclusiva en los tejidos blandos. Radiologicamente, es una lesion litica de aspecto agresivo con invasion a menudo considerable, de los tejidos blandos, que se visualiza muy bien mediante resonancia magnetica. En ausencia de tratamiento, el tumor ocasiona la muerte rapida debido a las metastasis a distancia, pulmonares y oseas. En la actualidad, el tratamiento se basa en la combinacion de quimioterapia y medidas locales, preferiblemente quirurgicas y, a veces, radioterapicas. Los dos factores pronosticos esenciales son la existencia de metastasis iniciales y la respuesta a la quimioterapia. Con el tratamiento actual, la probabilidad de supervivencia a los 5 anos sin recidiva es del 70 % en las formas locales y del 30 % en las formas metastasicas. Con los protocolos mas recientes, en particular con la quimioterapia en dosis altas asociada con el trasplante de hemocitoblastos, se intenta mejorar los resultados obtenidos en los tumores de pronostico desfavorable. Cabe esperar que los adelantos de la biologia molecular aportaran nuevos tratamientos terapeuticos.

SummaryBecause of the relative frequency of osteofibrous dysplasia (OFD) and the gravity of adamantinoma, it is important to know whether there is a link between these two entities. A young boy had been followed from the age of 5 years for OFD of the right tibia. At the age of 10, biopsy performed because of pain, revealed OFD-like adamantinoma. Surgery was undertaken, with en bloc proximal tibial resection of 14cm and reconstruction by free vascularized fibula and internal fixation. This observation illustrates the risk of evolution of OFD-like adamantinoma, showing the same unfavorable evolution as classic adamantinoma. Strict surveillance is mandatory in OFD, with systematic biopsy in case of onset of pain or increased tumor volume.

Resume Cette observation montre l’interet de la TEP/TDM au FDG dans la caracterisation de tumeurs mammaires bilaterales chez une femme jeune sans facteur de risque carcinologique.

Resume L'angiogenese constitue une etape essentielle de la croissance tumorale et de sa dissemination metastatique, assurant a la tumeur son apport nutritionnel et par le contact avec les lumieres vasculaires, son extension a distance. Sa survenue met en jeu un nombre eleve de molecules qui l'activent directement et qui interagissent avec la matrice extracellulaire. Les vaisseaux intratumoraux constituent un reseau irregulier comportant de nombreux shunts et leur paroi est anormale, incompletement recouverte de myocytes et pericytes, avec une membrane basale morcelee. Ces particularites morphologiques sont a l'origine, malgre l'abondance du reseau vasculaire, d'une moins bonne oxygenation de la tumeur, hypoxie qui genere la production de facteurs angiogeniques, creant une autoactivation. Le pathologiste est aujourd'hui aide a evaluer l'angiogenese par l'immunohistochimie. Celle-ci facilite la detection des vaisseaux par l'utilisation d'anticorps specifiques de l'endothelium (CD31, CD34, fVIII), permettant son evaluation quantitative ou « densite vasculaire ». Son importance apparait tres variable d'un patient a l'autre et a differents secteurs d'une meme tumeur, predominant generalement a sa peripherie. Malgre cette heterogeneite et la complexite des mecanismes en jeu, cette quantification est aujourd'hui un facteur pronostique independant de la plupart des tumeurs : plus celles-ci sont vascularisees plus le risque de dissemination metastatique augmente. L'immunohistochimie permet egalement l'evaluation d'activateurs (VEGF, FGF etc.) et celle de leurs recepteurs (VEGF-R). Leur quantification s'avere egalement etre pronostique mais cette analyse parait surtout utile a la selection des medicaments anti-angiogeniques qui seront bientot commercialises, mais necessitera une standardisation de ces techniques immunohistochimiques associee a la mise en place d'un controle de qualite externe.

To elucidate further the potential of a Semliki Forest virus (SFV) vector in vivo for gene therapy, we constructed a vector, SFV-IL12, to transfer murine IL-12 genes into tumors. A single intratumoral injection of established B16 murine melanoma with SFV-IL12 resulted in a significant inhibition of tumor growth, while injection with SFV-LacZ had no effect. This antitumoral activity correlated with an increase of IFN gamma production, MIG and IP-10 mRNA expression, both at the tumor site and at the periphery. In contrast, no increase in CTL- or NK cell-mediated cytotoxic response could be detected, ruling out the involvement of T and NK cell cytotoxicity. To determine how the transfer to IL-12 genes induced tumor regression, the antiangiogenic-activity of SFV-IL12 was investigated using Doppler ultrasonography (DUS). SFV-IL12 inhibited in situ neovascularization within the tumor, without affecting the resistance index of pre-existing intratumoral blood flows. In addition, histological analysis of SFV-IL12-treated tumors showed massive tumor necrosis induced by SFV-IL12 treatment. These data indicate that SFV-IL12 inhibits tumor growth through its antiangiogenic activity, demonstrated for the first time in vivo by DUS, and suggest that the SFV vector may be a novel valuable tool in tumor gene transfer.

Les marges de securite qui permettent de juger la qualite d’exerese d’une lesion mammaire constituent le principal marqueur pronostique de la rechute locale, avec le jeune âge et la presence d’emboles vasculaires tumoraux [1]. En raison de son importance sur le pronostic general aujourd’hui prouvee par differentes etudes [2], ce parametre prend une importance grandissante. C’est en effet le seul parametre pronostique que le clinicien peut directement modifier. Il est d’autant plus important qu’avec le developpement du depistage organise ou individuel, les lesions detectees sont de meilleur pronostic. L’amelioration generale du pronostic attendu par le depistage ne doit pas etre compromise par une mauvaise prise en charge locale a l’origine de rechute locale qui influerait sur le pronostic general. Il est egalement important en cas de carcinomes canalaires in situ car les recidives s’effectuent pour moitie sous forme infiltrante, exposant a une progression dans la maladie [3–6].

Dans le cancer du sein, l’apparition de metastases est signe d’incurabilite et releve d’un traitement medical dont deux modalites, l’hormonotherapie et la chimiotherapie, sont utilisees depuis des decennies et une, l’immunotherapie, d’utilisation recente, annonce les therapies ciblees. L’efficacite des traitements disponibles constatee quotidiennement est temporaire, modeste individuellement mais somme toute benefique par leur diversite.

Le cancer du sein, en raison de son incidence elevee et de son agressivite, a suscite la recherche active de facteurs de risque qui permettraient de mieux en comprendre les mecanismes de croissance et de prevenir et de limiter son developpement. Le risque histologique se definit pour une patiente chez qui vient d’etre diagnostiquee une lesion histologique benigne comme le risque de developper ulterieurement un cancer du sein associe a la nature et l’importance de cette lesion histologique. Les lesions dites « a risque » repondent aux lesions benignes dont le niveau de risque est eleve en comparaison avec le risque de la population generale.

Bien que les carcinomes canalaires et lobulaires soient les deux formes les plus frequentes de cancer infiltrant du sein, d’agressivite sensiblement comparable, ils s’opposent sur de nombreux points. Ainsi, la forme lobulaire voit son incidence augmentee par l’exposition aux differents traitements hormonaux. L’infiltration du tissu mammaire qu’elle occasionne est majeure, depassant souvent les estimations cliniques et radiologiques, a l’origine des tailles importantes observees. Ses caracteristiques biologiques sont celles d’une tumeur bien differenciee, faible taux de proliferation, forte expression pour les recepteurs hormonaux, absence d’anomalie de la p53, de la voie d’apoptose ou d’hyperexpression d’Her2. Les sites metastatiques different egalement avec une predilection pour les sereuses (peritoine, meninges) pour la forme lobulaire. Enfin, il semblerait que cette forme reponde moins bien a la chimiotherapie que la forme canalaire en neo-adjuvant (33, 34). Toutes ces differences inciteraient a developper des attitudes therapeutiques et des modalites de surveillance differentes.

The process of tumor neoangiogenesis plays a central role in the growth and spread of tumors. It is currently a leading theme in oncology, and many new drugs targeting the tumor neoangiogenic process are under development. Expanding tumors become hypoxic and tumor cells express transcription factors, such as the hypoxia-inducible factor (HIF), which induce the release of proangiogenic growth factors such as vascular endothelial growth factors (VEGF) and transforming growth factors that promote the formation of new capillaries by recruiting, activating, and stimulating endothelial cells. Activated endothelial cells secrete matrix metalloproteases, which degrade the basement membrane and the extracellular matrix, and adhesion receptors such as integrins alphavbeta(3), which allow their migration into the extracellular matrix toward the tumor cells. The newly grown vessels are immature and differ from normal capillaries. They are tortuous and irregular, resulting in poorly efficient perfusion, they are leaky (especially to macromolecules), and they are independent of the normal mechanisms of regulation of the capillary blood flow. Moreover, tumor microcirculation is heterogeneous. Evaluation of angiogenesis can be used as a prognostic marker to evaluate the aggressiveness of tumor and as a potential predictive marker of antiangiogenic treatment response. Histopathologic techniques of microvascular density indexes require invasive tissue sampling and need to be standardized. Hemodynamic characteristics of immature neovessels can be noninvasively assessed by dynamic contrast-enhanced magnetic resonance imaging or computed tomography. Tissue enhancement depends on arterial input function, kinetic of distribution of blood into the capillary bed, leakage across the capillary walls, and volume of the interstitial space. Pharmacodynamic models allow the evaluation of microvascular parameters of tissue blood flow, tissue blood volume, tissue interstitial volume, mean transit time, and permeability by surface of capillary wall. Methods based on dynamic contrast enhancement have been shown to correlate with conventional outcome methods such as histopathologic studies and survival. Radiologists must be convinced that, by using this emerging and promising approach, it is becoming possible to gain functional information during routine tumor imaging.

Angiogenesis is an essential step of the tumoral growth and of the metastatic dissemination. It provides the nutriments necessary to the tumor and by the direct contact of the lumen vessels, facilitates its metastatic extension. The activation implies a large number of different agents which closely interact with the extracellular matrix. The intra tumoral vessels constitute an irregular network with numerous shunts. Their wall is also abnormal, incompletely covered by pericytes, and their basal membrane is thin and fragmented, sometimes absent. These features are responsible for an increased permeability and despite the large number of vessels, deserve a less effective oxygenation. The hypoxia induced secondarily activates the synthesis of angiogenic factors. The pathologist receives today help from immunohistochemistry for the evaluation of angiogenesis. This means facilitates the detection of vessels by use of specific antibodies directed against the endothelial cells (CD31, CD34, fVIIIrag...). It also allows the quantification of vessels or "microvascular density". Its importance varies from one patient to another and for different areas of a same tumour, the "hot-spot" generally located at its periphery. Despite its heterogeneity and the complexity of mechanisms involved in the regulation, the microvascular density appears to be an independent prognostic factor for tumour of different histological types. Immunohistochemistry also permits the evaluation of different characteristics of vessels and the tumour such as the activators (VEGF, FGF...) or their specific receptors (VEGF-R). Such analysis is also important for the determination of the prognosis but appears more interesting for the selection of the antiangiogenic treatment. However, this step will require the standardization of the immunohistochemistry techniques and the implementation of an external quality control.

The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients.Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers.The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

The development of cancer screening has led to the discovery of smaller tumours and less frequent dissemination to lymph nodes and organs that requires special techniques for detection. Numerous papers on micrometastases reflect a considerable amount of work devoted to detection methods, technical problems and the prognostic value of these lesions. Apart from cytological techniques, the pathologist can rely on two methods for the detection of micrometastases: serial slicing of paraffin-embedded blocks and immunohistochemistry. When these methods are combined, the detection rate is similar to that of biological methods and can attain levels as high as 60% for the sentinel node with the added vantage of being able to visualise cells. Despite an impressive body of studies, major disparities are found in detection rates and the prognostic value of micrometastases is not firmly established. In order to facilitate comparisons and analyses, it is essential to adopt a common terminology with precise definitions. The UICC advocates the use of the term micrometastasis which denotes a metastasis smaller than or equal to 2 mm in size. The potential aggressiveness of micrometastases is dependent on other poorly explored parameters such as the number of cells detected in the bone marrow or lymph node and the location of micrometastases. The new pTNM classification takes into account this latter parameter and distinguishes two categories of micrometastases: "isolated tumor cells" located in the lumen of vessels or sinuses and "micrometastasis" which has already invaded an organ. This classification warrants further analysis to determine the prognostic value of these categories. The next challenging problem consists in determining the key biological properties that account for distant dissemination.

Based on encouraging results reported in alternating radiotherapy and chemotherapy in inflammatory breast carcinoma, we have tried in this study to optimize locoregional treatment with a hyperfractionated accelerated radiotherapy schedule alternating with chemotherapy.From May 1991 to May 1995, 54 patients, previously untreated, with non-metastatic inflammatory breast cancer were entered in an alternating protocol consisting of eight courses of combined chemotherapy and two series of loco-regional hyperfractionated accelerated radiotherapy with a total dose of 66 Gy. Hyperfractionated accelerated radiotherapy was started after three courses of neoadjuvant chemotherapy (Adriamycin, Vincristine, Cyclophosphamide, Methotrexate, 5-fluoro-uracile) administered every 21 days +/- G.CSF. The first series delivered 45 Gy/three weeks to the breast, the axillary, subclavicular and internal mammary nodes, with two daily sessions of 1.5 Gy separated by an interval of eight hours; the second series consisted of a boost (21 Gy/14 fractions/10 d) alternating with another regimen of anthracycline-based-chemotherapy (a total of five cycles every three weeks). Hormonal treatment was given to all patients.Of the 53 patients evaluated at the end of the treatment, 44 (83%) had a complete clinical response, seven (13%) had a partial response (50%) and two (4%) had tumoral progression. Of the 51 patients who were locally controlled, 18 (35%) presented a locoregional recurrence (LRR); eight (15%) had to undergo a mastectomy. All the patients but two with LRR developed metastases or died of local progressive disease and 26 (50%) developed metastases. With a median follow-up of 39 months (range: 4-74 months), survival rates at three and five years were respectively, 66 and 45% for overall survival and 45 and 36% for disease-free survival.Alternating a combination of chemotherapy and hyperfractionated accelerated radiotherapy is a well-tolerated regimen which provides acceptable local control. The systemic dissemination remains the major problem of inflammatory breast carcinoma and further clinical trials using alternative drug regimens are warranted.

Malignant pheochromocytomas are rare in childhood and the prognosis of children with this tumor is not well known. We present 2 pediatric observations of malignant pelvic pheochromocytoma. Symptoms in both cases were headache and hypertension. The tumor invaded the sacral bone. Angiogram helped to localize the tumor and metastases, and allowed preoperative embolization of the tumor in 1 case. The first child underwent incomplete surgical resection, (131)I-MIBG therapy and radiotherapy, and is still alive 2 years after diagnosis. The second child died from metastatic invasion a few weeks after discovery of the tumor. We reviewed previous reports of children with malignant pheochromocytomas (30 cases). Primary tumor was extraadrenal in 50% of cases. The 3-year survival rate was 73 +/- 9% (mean +/- SD). Apart from surgical resection, no particular treatment appeared to be more effective than others in reducing mortality.

E-cadherin is a prominent factor in maintaining the epithelial architecture, and loss of its normal function is considered to be a key element in cancer invasion. In breast cancer, correlation between alteration of E-cadherin expression and histological type has been reported, but associations with other parameters remain uncertain. To refine these findings and to explore the biological significance of features thought to result from alterations of cell-to-cell adhesion systems, rare in sporadic cases but more frequent in BRCA1-associated breast cancers (BRCA1-BCs), we investigated E-cadherin expression by immuno-histochemistry in a combined panel of 214 breast cancers enriched in hereditary cases (176 sporadic cases and 38 BRCA1-BCs). Following multivariate statistical analysis using a logistic regression model, only 2 parameters were significantly associated with loss of E-cadherin expression: lobular histological type (p0.0001), in agreement with previous results, and syncytial growth pattern (SGP) (p = 0.01). The latter result provides a biological basis for SGP, the cardinal feature of medullary breast carcinoma.

Since there is a lack of common family profile among BRCA1-gene carriers, and since the risk of being a mutation carrier is not limited to women with a family history of breast or ovarian cancer, multivariate statistical analysis using the logistic-regression model was carried out, to discriminate between sporadic cases and BRCA1-breast cancers (BRCA1-BCs), especially when information about the family history of breast/ovarian cancer and ethnicity are irrelevant or unavailable, in order to offer specific medical treatment to this population. We examined 32 BRCA1-BCs selected at cancer genetic clinics and 200 consecutive controls without family history of breast cancer for age at onset and current morphological parameters. Following the multivariate analysis, 3 parameters only, namely, early age at cancer onset [odds ratio (OR) for each year = 1.16; p0.0001], estrogen-receptor negativity (OR = 5.7; p = 0.01) and poor differentiation (OR = 5; p = 0.03) were found significant factors for predicting BRCA1-carrier status. The expected impact in BRCA1 screening of our model was estimated using data on 5700 breast-cancer cases from a hospital-based registry. Only 50 and 15% of tumours with early age at onset below 35 years present one or the other 2 discriminant parameters respectively. Consequently, whereas the probability of finding a BRCA1 mutation is rated low (6.2%) when the sole criterion of early onset up to the age of 35 years is used, based on our model, in the sub-group of women with a tumor that is both estrogen-receptor-negative and poorly differentiated the mutation-detection rate is predicted to be above the 10% chance level recommended by the ASCO guidelines. This sub-group of women, representing about 1% of all breast-cancer cases in Western countries, consequently deserves to be tested.

Carcinomas are by far the most frequent malignant tumors of the breast. Screening by mammography has considerably increased the number of breast biopsies for mammographic abnormalities without a palpable mass. The role of the pathologist is to: 1. accurately diagnose specimens and ensure quality control, and 2. provide clinicians with all the informations required for staging and appropriate treatment without being led astray by the new prognostic factors based on biological markers in fashion.

More than 50% of malignant soft tissue tumors recur locally [2, 6]. There are several reasons for these disastrous results. Since benign tumors are 100-fold more frequent than malignant ones [6], the latter are frequently not suspected until after initial surgery, resulting in inadequate margins and microscopic residual nodules. The general surgeon who operates on many benign soft tissue masses takes tremendous precautions to preclude functional sequelae in patients. Most often he attempts to enucleate the lesion, particularly as most malignant tumors look macroscopically well limited, with a pseudocapsule, giving the erroneous impression of being benign. In fact, however, multiple, sometimes small, nonpalpable satellite nodules, often at the periphery of the main mass are discovered only at histologic examination after the operation is over, and these tiny lesions may account for the frequency of local recurrence. The histologic analysis of malignant soft tissue tumors is a formidable task, for more than 50 subgroups have been recognized [6]. In practice, every malignant soft tissue lesion (because of size or location criteria) should be sent to a reference center for evaluation and biopsy.

The aim of this study is to determine the diagnostic value of magnetic resonance imaging in the diagnosis of local recurrence of breast cancer. From 1991 to 1994, 61 women were studied prospectively using magnetic resonance imaging. All examinations were made on a 1.5 Testa machine with T1 weighted images and after gadolium-dota injection and dynamic images (T1 weighted sequences every 47 seconds during injection of a gadolinium-dota bolus). All the pre-injection, images in the dynamic series were subtracted from the images after injection. A surgical biopsy was obtained in 39 patients yielding a diagnosis of local recurrence (n = 28) or a benign lesion (n = 11). Among the 28 local recurrences, pathology examination reported invasive cancer in 22 and intra-ductal carcinoma in 6. In 22 patients with normal magnetic resonance imaging, follow-up examinations were performed every 6 months. There were no local recurrences within a delay of 6 to 36 months. Twenty-six of the 28 patients with a local recurrence, cystosteatonecrosis and surgery scar tissue less than 6 months old showed contrast uptake 1 min and 34 s after gadolinium injection during the dynamic sequence. This product uptake yielded nodular images within the invasive carcinomas and linear images in the intraductal cancers. In all cases, it is easier to visualize this contrast uptake in subtraction images. In conclusion, magnetic resonance imaging is a simple reliable method for the diagnosis of local recurrence of breast cancer.

As breast cancer screening programmes gain momentum, there is a parallel increase in histological problems mainly related to the identification of an increasing number of "borderline" breast lesions. The results of recent studies are often inconsistent, and bear witness to the lack of a consensus regarding the interpretation of both ductal and lobular epithelial hyperplasia. The authors insist on the need for an adequate number of samples and an irreproachable histologic technique which is indispensible if the morphologic subtleties, currently the only valid factors permitting the diagnosis, are to be appraised. The role of the pathologist is therefore crucial in the management of specimens which are entrusted to him and in helping the clinician to tailor treatment to fit each individual patient.

Pathologists have associated calcium oxalate dihydrate (weddellite) in breast biopsy specimens with benign or borderline lesions and rarely with malignancy. These microcalcifications may have a polyhedral shape in histologic specimens owing to their crystalline structure. A retrospective radiologic-histologic correlation study was performed on 300 clusters of microcalcifications to determine if microcalcifications with a polyhedral shape could be found at mammography. In 19 cases (6.3%), polyhedral microcalcifications (PMs) were detected by two radiologists. In 12 of these 19 cases, weddellite crystals were found in the histologic specimen under polarized light; in seven cases, no calcification was found. Although rare, PMs can be found at mammography by radiologists aware of their existence. They are due to weddellite crystals and in this series were associated with benign disease in 89% of cases. Prospective studies are required to determine the frequency of PMs on screening mammograms and to evaluate their negative predictive value.