Christophe Bergeron

Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing.

Background The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. Methodology/Principal Findings From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). Conclusions/Significance The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas.

Preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas: Final results of BSG 98 prospective trial

Radiation therapy remains the only treatment that provides clinical benefit to children with diffuse brainstem tumors. Their median survival, however, rarely exceeds 9 months. The authors report a prospective trial of frontline chemotherapy aimed at delaying radiation until time of clinical progression. The aim was to investigate the possibility that radiotherapy would maintain its activity in children whose disease progressed after chemotherapy. Twenty-three patients took part in this protocol, the BSG 98 protocol, which consisted of frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules. Each cycle included three courses delivered monthly; the first course was 1,3-bis(2-chloroethyl)-1-nitrosoureacisplatin, and the second and third were high-dose methotrexate. Three patients underwent one cycle; 5 patients each, two and three cycles; and 10 patients, four cycles. Twenty of the 23 patients eventually received local radiation therapy. A historical cohort of 14 patients who received at least local radiation therapy served as controls. Four patients experienced severe iatrogenic infections, and 11 patients required platelet transfusions. Median survival increased significantly in patients participating in the protocol compared to that in the historical controls (17 months, 95% confidence interval [CI], 10-23 months, vs. 9 months, 95% CI, 8-10 months; p = 0.022), though hospitalization was prolonged (57 vs. 25 days, p = 0.001). Although frontline chemotherapy alternating hematotoxic and nonhematotoxic schedules significantly increases overall median survival, its cost from infection and hospitalization deserves honest discussion with the children and their parents.

A 22-year French experience with solid tumors in children with Down syndrome.

Malignant solid tumors have rarely been reported in children with Down syndrome (DS) and are not well known. The authors collected from 1980 to 2001 all cases of solid tumors observed in DS patients aged from birth to 19 years within the network of the Société Française dOncologie Pédiatrique (SFOP). Only 21 cases were observed, with a peculiar distribution: a lack of intracranial tumors and embryonal neoplasms combined with an overrepresentation of lymphomas and germ cell tumors. The treatment of solid tumors in DS is difficult, due to physical and psychological impairments, different pharmacogenetic profile, and associated malformations.

Detection of N-myc amplification by FISH in immature areas of fixed neuroblastomas: more efficient than Southern blot/PCR.

N‐myc amplification is a major prognostic factor in neuroblastomas and is systematically investigated by Southern blot or polymerase chain reaction (PCR). A retrospective study of N ‐myc amplification has been carried out using fluorescence in situ hybridization (FISH) in 97 fixed neuroblastomas. For each tumour, FISH was performed on the area that contained the most immature neuroblasts. Among these 97 neuroblastomas, 16 were amplified and 12 were not interpretable. FISH was not interpretable in six cases. All neuroblastomas with N‐myc amplification detected by Southern blot/PCR were amplified with FISH, except three that were not interpretable. Four tumours that were not interpretable in Southern blot/PCR contained more than five copies of N‐myc by FISH: one was aneuploid and three were truly amplified, containing more than ten copies of N‐myc. Among these three patients, two died in a short time of their tumours. Ten cases were not amplified by Southern blot/PCR and showed more than five copies by FISH: four were aneuploid and two showed heterogeneous amplification, with a few cells clearly amplified whereas most were not. Four cases were amplified, of which two patients died of their tumours. This study confirms that when applied to the most immature areas of fixed neuroblastomas, FISH displayed a higher sensitivity than molecular techniques (p < 0.001) and could detect heterogeneous amplification. FISH could therefore become an important complementary procedure in assessing prognosis in neuroblastomas. Copyright

Case Report: A Preterm Infant with an Extradural Myxopapillary Ependymoma Component of a Teratoma and High Levels of α-Fetoprotein

The sacrococcygeal region may be the origin of germinal tumors, of paragangliomas, and, rarely, of extradural myxopapillary ependymomas (MPE) in the newborn and child. A case is presented of a preterm child with an abdominal tumor, originating from the precoccygeal area, that turned out to be a teratoma with a component of an MPE. The high levels of alpha-fetoprotein in this preterm baby were initially misleadingly interpreted as a tumoral marker. The differential diagnosis and the difficulties in interpreting tumoral markers in infants are discussed.

8 Management of paediatric lymphoma

The high cure rate obtained in most paediatric lymphomas allows an optimistic vision of future treatments, with decreased primary late effects observed in patients who have completed therapy: decreased cognitive functional impairment, reproductive dysfunction, poor social adaptation, and risk of second malignancies. The deleterious effects of radiation therapy on neurocognitive functions is now well documented (Meadows et al, 1981) but, apart from rare acute toxicities (Sasazaki et al, 1992), reports on those following high-dose methotrexate are scarce, and sometimes discordant (Jannoun and Chessels, 1987; Robertson et al, 1992). Longer follow-up evaluation is warranted before definitive conclusions concerning the relationship between computed tomography scan findings and clinical outcome can be reached. The reproductive function of males is much more severely altered than that of females (Jaffe et al, 1988). Several reports have demonstrated the major dose-dependent toxicity of alkylating agents on male fertility. Male patients receiving more than 9 g/m2 of cyclophosphamide have a particularly high risk of sterility (Aubier et al, 1989) and children with less than 4 g/m2 of cyclophosphamide, a very low risk Patte et al, 1996a). Women treated before the age of 20 who do not receive abdominal irradiation usually have normal reproductive function, although early puberty (Quigley et al, 1989) and early menopause (Byrne et al, 1992) have been documented. The risk of a second malignancy is not as great as in children with a solid tumour or Hodgkins disease (Anderson et al, 1993). The risk is higher in patients treated with alkylating agents (Lemerle et al, 1989). With the increasing cure rate, a social problem may arise for adults who have had cancer. The increased awareness by politicians and health insurance companies should help to solve, at least partially, this new problem (Monaco, 1987). As cure rates increase, emerging concerns involve the familial repercussions of this heavy treatment (Lansky et al, 1978; Cairns et al, 1979). At this stage, there is no demonstrated deleterious effect from treatment for the progeny of cured children (Mulvihill et al, 1987; Stein, 1993). Cure of children with lymphoma is a reality, and one should think in terms of complete cure when facing a distressed child with a heavy tumour burden arriving for diagnosis (Schweisguth, 1979). Since 1980, the progress of molecular biology techniques has permitted the precise molecular characterization of gene alterations (oncogenes, immunoglobulins, and T-cell receptor genes) involved in the process of malignant transformation of normal lymphocytes (Bhatia et al, 1996; Williams et al, 1996). In parallel, treatment of malignant NHL of childhood has improved dramatically. The progress in molecular biology has not led to a modification of the clinical management of NHL of childhood which remains mainly empirical. Precise cytohistological classification of lymphomas has resulted in the characterization of low- and high-risk patients requiring distinct therapeutic approaches. The major goals of the next few years will be to increase the cure rates of those patients with CNS and bone marrow involvement at diagnosis, probably through an intensification of chemotherapy (increase in the dose or intensity of the chemotherapy); to define precisely subgroups of good-prognosis patients requiring less aggressive treatment that would decrease the risk of long-term events; and to salvage previously heavily treated patients at relapse. The precise analysis of gene alterations in lymphoma cells of a given patient may have important clinical applications in this respect (Bhatia et al, 1996).

Tumeur stromale gastro-intestinale chez l'enfant. À propos d'un cas et revue de la littérature

Stromal gastrointestinal tumors or GIST are undifferentiated mesenchymal tumors of gastrointestinal tract that showed characteristic c-kit expression. GIST are very rare in children and only 21 cases are reported in literature. The authors present a GIST arising in the stomach of a 7-year-old girl and revealed by severe anaemia. The patient underwent surgical resection and chemotherapy because of high-risk markers. Positive diagnosis and prognosis of paediatric GIST are discussed with literature data.

Antiangiogenic effects in patients with progressive desmoplastic small round cell tumor: data from the French national registry dedicated to the use of off-labeled targeted therapy in sarcoma (OUTC’s)

BackgroundDesmoplastic small round cell tumor (DSRCT) is a very rare mesenchymal tumor that mainly affects teenagers and young adults with a mean age at diagnosis around 20–25xa0years. Although initial management still needs standardization, many centers will use multimodal treatment including intensive chemotherapy, extensive surgical resection followed by radiotherapy. Despite this, prognosis remains very poor and the median overall survival is 25xa0months. Recurrent disease is mainly treated by chemotherapy. Recently, due to the unmet medical need for recurrent disease, targeted therapies were explored for DSRCT.MethodsIn this study, we assessed the response rate and progression free survival in nine cases of progressive DSRCT included in the OUTC’s registry and treated with antiangiogenics targeted agents (sunitinib, sorafenib and bevacizumab). OUTC’s, a French national registry, collects data about the use of off-label targeted therapy in sarcoma.ResultsEight males and one woman were included, with median age at diagnosis of 27.3xa0years (range from 9 to 48xa0years). They received a mean 3 lines (2–5) of treatment before antiangiogenic agent initiation. Six patients received sunitinib, two received sorafenib and one bevacizumab. Median progression free survival was 3.1xa0months (range 2–5.5xa0months) and best response observed was 5.5xa0months stable disease. Most patients had manageable low-grade toxicities, mainly fatigue, abdominal pain and skin toxicity.ConclusionsDespite very limited activity of antiangiogenics in our study, prospective collection of cases of these rare tumors together with molecular data should guide therapeutic decision and enhance outcome.

SHOULD NASAL-PARANASAL-ORONASOPHARYNGEAL LYMPHOMAS IN CHILDREN BE CLASSIFIED DIFFERENTLY FROM THE OTHER LOCALIZATIONS?

Since 1975, improvements in chemotherapy and dose intensi® cation have transformed the outcome in non-Hodgkin lymphoma (NHL). Childhood NHL differs from adults in that it usually behaves aggressively, both clinically and histologically, and often presents at an extranodal location. The Children’s Cancer Group (CCG) study (CCG-551) [1] has shown that treatment should be adapted according to immunology. Moreover, high-dose methotrexate in combination with systemic treatment increases the outcome and decreases the incidence of central nervous system (CNS) relapse [2]. In a previous issue of Pediatric Hematology and Oncology [3], Yaris et al. report retrospectively their experience in treating 55 children with nasal ± paranasal ± oronasopharyngeal (NPONP) NHL. The study period was 23years, and 7 different regimens were used to treat these patients. We agree with the authors that intrathecal treatment and doxorubicin are important components in lymphoma treatment and that early stage disease (I or II), whatever the system classi® cation, requires aggressive chemotherapy. The most important prognostic factor in NHL is the treatment received. The authors have also compared the St. Jude classi® cation [4] and the TNM staging system [5] and conclude that the TNM system is more accurate for NPONP lymphomas in children. We are not convinced by this conclusion. The aim of staging and subsequent classi® cation is (1) to de® ne the exact disease extent, (2) to adapt the treatment accordingly, (3) to de® ne subgroups according to prognostic factors, and (4) to compare international patient populations. All classi® cation systems share simplicity and each has its own individual problems. In particular, in childhood lymphomas, not only the extent of the disease but also the cellular characteristics (T or B cell) have to be considered. The following questions would be answered.