Clinical trials of adjuvant treatment of breast cancers have been limited for a long time to overall comparisons of heterogeneous populations. A new generation of clinical trials should be implemented, with especially the selection of the patients as a function of the molecular characteristics of their tumour. Unquestionable biological data must be taken into account to raise relevant questions, such as the role of topoisomerase II in the response to anthracyclines or the role of p53 in the response to taxanes. Microarrays technology, which allows the establishment of expression profiles of the whole genome, are very powerful tools which have allowed to reclassify breast tumours and to obtain "molecular signatures" characteristic for the risk of metastatic recurrence. A large randomised prospective study has been recently initiated with the aim of comparing the prognostic value of this signature to that of classical histopathologic criteria. In the next future, it will be possible to consider an individualisation of the prescription of cancer chemotherapies on molecular validated bases.

Retinoblastoma is the most frequent eye tumor in children, with an incidence of 1/15 000 births. Sixty per cent are unilateral: the median age at diagnosis is 2 years and most of these forms are not hereditary. Retinoblastoma is bilateral in 40%: the median age at diagnosis is 1 year. All bilateral and multifocal unilateral forms are hereditary. Hereditary retinoblastoma constitutes a cancer predisposition syndrome: a subject carrying a constitutional RB1 gene mutation has a greater than 90% risk of developing retinoblastoma, but is also at increased risk of developing secondary cancers. The 2 most frequent revealing symptoms are leucocoria and strabismus. Diagnosis is made by fundoscopy. US, MRI, CT scans may contribute to diagnosis. Management of patients with retinoblastoma must take into account the various aspects of the disease: the visual risk, the possibly hereditary nature of the disease and the life-threatening risk. Enucleation is still often necessary in unilateral disease; adjuvant treatment is decided according to the histological risk factors. Conservative treatment of at least 1 eye is possible in most of the bilateral cases: laser alone or combined with chemotherapy, cryotherapy and brachytherapy. The indication for external beam radiotherapy should be restricted to large ocular tumors and diffuse vitreous seeding because of the risk of late effects, including secondary sarcoma. Long-term follow-up and early information to retinoblastoma patients regarding the risk of second primary tumors and transmission is actually important.

Myelofibrosis with myeloid metaplasia (MMM) is a rare myeloproliferative disorder (MPD) characterized by clonal proliferation of hematopoietic progenitors. 40-50% of karyotypes on blood (or more rarely on bone marrow) revealed at least one abnormality: 30% at diagnosis and 90% in blastic transformation phase. A minority of patients with newly diagnosed polycythemia vera (PV) presented chromosomal abnormalities in their myeloid cells. The most frequent visible alteration in MMM and PV is a 20q deletion, also characterized in other MPDs and myeloid malignancies. Among other chromosomal changes, deletion 13q is more common in MMM than in other MPDs, trisomy 9 and 9p alterations appear more frequent in PV. Cytogenetic studies have disclosed cryptic anomalies and pointed out the high frequency of 9p alterations. JAK2 (V617F) mutation was found in almost all PV patients and near half of MMM patients. This molecular abnormality takes an increased importance in the knowledge of the physiopathology of MPDs, particularly in PV and also in prognosis of MMM patients.

Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer.

Ganglioglioma is usually a well differentiated slowly growing mixed neuronal and glial neoplasm corresponding to WHO grade I or II. However, some gangliogliomas are considered to be WHO grade III because they exhibit anaplastic features in their glial component. Finally there are exceptionally rare cases of newly diagnosed gangliogliomas with grade IV changes in the glial component. We report a case of a 25-year-old woman with a family history of neurofibromatosis who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell multiform tumor glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period. Histologically, two cell populations were noted: a predominant glial component consisting in a multiform glioblastoma and ganglion cells supporting a diagnosis of ganglioglioma. Immunohistochemical analysis clearly distinguished the two tumor cell populations. Although other cases of grade III gangliogliomas and twelve cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the second case of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histological findings in a multiform glioblastoma and a ganglioglioma. It also documents the aggressive biologic behavior of this complex neoplasm.

We report a case of a de novo acute basophilic leukaemia, revealed by an infectious pneumopathy in a 73 year old man. The full blood count revealed an hyperleucocytosis associated with an unregenerative normocytic normochrom anaemia and a thrombocytopenia. The blood and bone marrow smears showed a mixture of undifferentiated blast cells and basophiloblasts (high nucleo-cytoplasmic ratio, coarse basophilic cytoplasmic granules), along with basophilic precursors and basophilic polymorphonuclears. All the blasts were MPO negative but positive for the toluidine blue metachromatic coloration, which is considered as consistent with basophilic lineage. Immunophenotypic studies showed myeloid blasts, without maturity marker, CD 117 negative and CD203 cytoplasmic positive, the latter known to be highly representative of the basophilic lineage. This very clear-cut phenotype, associated with the morphology of cells, were arguments to ascertain the basophilic lineage of the blasts without the need of electron microscopic study. Cytogenetic and RNA analysis revealed the presence of a Philadelphia chromosome and of a BCR-ABL transcript with the unusual junction e6a2. Thus, imatinib was added to the conventional chimiotherapy and the patient is currently in complete remission. This clinical prompted allows us to review the literature on acute basophilic leukaemia and to state on the different diagnostic criteria of this rare disorder.

The proliferation of prostate cells appears to be influenced by two steroidal hormones: testosterone and vitamin D, whose action appears to mediated by their respective receptors. The genes coding for these two receptors and the gene coding for 5-alpha-reductase (enzyme involved in testosterone metabolism) have been identified as candidate genes for prostate cancer predisposition. Previous epidemiological and genetic susceptibility studies have reported controversial results concerning the role of these genes on prostate cancer incidence in various populations. The objective of this study was to determine the possible association in this population between polymorphisms of these genes, and the clinical and pathological stage and grade of prostate cancer.

Non-functional paraganglioma have not clinical or biological characteristics, so that the diagnostic is most of the time delayed and made on the occasion of advanced abdominal tumor or symptomatic metastasis management. Hereditary forms, notably those with SDHB mutation, seem to have a poor prognosis. On the other hand, and on the oposite to sporadic forms, they are the only ones to benefit from genetic testing which make possible, if positive, an earlier diagnostic, before apparition of symptoms, recurrence or metastasis. We report a case of non-functional malignant hereditary paraganglioma diagnosed belatedly and we will consider management problems raised by non-functional forms.

Soft tissue non lymphoid malignant round cell tumors observed in children and adolescents are rare and are very different from adult tumors. They are often undifferentiated and distinctive key morphologic features are often lacking, but, on the other hand, specific recurrent genetic alterations, mostly translocations, are distinctive. Immunohistochemical features are also important for the diagnosis, and there is sometimes a strong correlation between the presence or the absence of an immunoreactivity for a specific protein and the presence of a specific genetic alteration. Finally, careful morphologic histological examination and immunohistochemical features will lead to a diagnosis which will be often confirmed by cytogenetics (translocations) or molecular techniques (fusion transcripts, deletion, mutation).

Serrated neoplasia of the gastro-intestinal tract have peculiar microscopic and molecular features that are still incompletely described. Some serrated polyps seem to be involved in a new carcinogenic pathway in the colon: the serrated neoplasia pathway, with hypermethylation of the cytosine-guanine dinucleotides, located in the promoter of some genes such as h-MLH1, BRAF and MGMT. The natural history of the serrated polyps and their risk for progression to malignancy are still unclear. There is no official guideline for the management of serrated polyps. The aim of this article is to describe the epidemiological, morphological, immunohistochemical and molecular characteristics of the serrated neoplasia of the gastrointestinal tract: hyperplastic polyps, "traditional" serrated adenomas, mixed hyperplastic and adenomatous polyps, sessile serrated adenomas, hyperplastic polyposis and serrated adenocarcinomas.

The benefit of colorectal cancer screening in the average-risk population, as well as in the presence of high risk genetic predispositions, has been validated by a significant reduction of the mortality associated with the disease. Several screening options are recognized and compliance with these measures remains a public health problem. The physician plays a key role in the promotion of the colorectal cancer screening. Collecting a precise family history is crucial for the identification of individuals at high risk. Validated clinical criteria are helpful for the identification of individuals with a genetic predisposition to colorectal cancer. Molecular screening for the main colorectal cancer predisposing genes should now be integrated in the clinical management of these patients and their families.

One of the major risk factors for developing breast cancer is a positive family history for this disease. A detailed family history is critical for breast cancer risk evaluation and for evaluation of the probability of a genetic predisposition to breast cancer in the family (the hereditary breast/ovarian cancer syndrome). Various models have been developed to evaluate these risks. The diagnosis of a low, moderate or high breast cancer risk is associated with adapted breast cancer screening procedures. Screening with magnetic resonance imaging (MRI) is recommended only for women identified as high risk. Genetic testing of the main breast cancer susceptibility genes, BRCA1 and BRCA2, is now available in a clinical setting.

PST (primary systemic therapy) represents the standard treatment of care for patients with LABC (locally advanced breast cancer). There is also an emerging role of PST in the treatment of operable breast cancer. In both situations, clinical and pathological responses, in particular when complete, are good predictors of outcome. Identifying the factors predicting response to PST would help clinicians of selecting the most appropriate treatment. There is thus a need for clinical and molecular factors predictive of response. Unfortunately, none of the molecular markers identified in breast tumors is recommended for a use in routine, with the exception of ER and HER2 respectively predictors of response to hormone therapy and Herceptin. New technologies like DNA microarrays are likely to provide in a next future surrogate markers of response to PST in Breast Cancer.

Major advances have been made in the understanding of the genetic mechanisms underlying endocrine tumorigenesis, through the study of several syndromes of genetic predisposition and the identification of the genes involved. The syndrome of type 1 multiple endocrine neoplasia (MEN-1) is one of the best known; this autosomal dominant hereditary syndrome predisposes to the development of endocrine tumors of the pituitary, the parathyroids, the foregut and the adrenals. The responsible gene, known as MEN-1, encodes an original protein, menin, involved in several major cellular functions, such as the control of cell proliferation and differentiation. Type 2 multiple endocrine neoplasia (MEN-2) is an autosomal dominant hereditary syndrome associated with the development of medullary carcinomas of the thyroid, pheochromocytomas and hyperparathyroidism; the corresponding gene, RET, encodes a transmembrane receptor with tyrosine kinase activity. Endocrine tumors are also associated with non Hippel-Lindau disease and with phacomatoses, such as type 1 neurofibromatosis and tuberous sclerosis. Finally, isolated familial syndromes of endocrine tumors have been described: isolated familial hyperparathyroidism type II (HRPT2), associated with alterations in a gene coding for an original protein, parafibromin, or isolated familial syndromes of pheochromocytomas and paragangliomas (PRG) associated with mutations in the genes SDHB, SDHC or SDHD, which encode succinate-dehydrogenase subunits. The understanding of the genetic mechanisms underlying these syndromes of predisposition is essential for the diagnosis and management of these patients and their family; it also gives insight on the molecular mechanisms of endocrine tumorigenesis.