Patrizia Dall’Igna

Prognostic stratification for children with hepatoblastoma: The SIOPEL experience

PURPOSE To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient. PATIENTS AND METHODS Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP < 100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP > 1,200,000 ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS). RESULTS In 541 patients, reduced EFS correlated significantly with AFP < 100 ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16-7.75), AFP ≥ 1.2 × 10(6)ng/mL (2.48, 1.47-4.17), metastatic disease (3.02, 2.05-4.44), PRETEXT IV (2.15, 1.19-3.87), multifocality (1.59, 1.01-2.50), age > 5 years (2.76, 1.68-4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91-5.77); but not with PRETEXT III, age 30-60 months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3 year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age> 5 years and/or AFP > 1.2 × 10(6) have 3 year EFS of 71% and SCU and/or AFP < 100 ng/mL and/or metastatic have a 3year EFS of 49%. CONCLUSION Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Pancreatoblastoma: A report from the European cooperative study group for paediatric rare tumours (EXPeRT)

BACKGROUND Pancreatoblastoma is a very rare malignant tumour typically occurring in the early years of life. Due to its rarity, standardised diagnostic and therapeutic guidelines are not available for pancreatoblastoma. METHODS The newborn cooperative group denominated EXPeRT - European cooperative study group for paediatric rare tumours - combined in a joint analysis of all cases registered between 2000 and 2009 by the national groups of Italy, France, United Kingdom, Poland and Germany. RESULTS Twenty patients <18years old (median age 4years) were analysed: nine had distant metastases at diagnosis. Seventeen patients had tumour resection, at initial or delayed surgery. Eighteen received chemotherapy (response rate 73%), seven received radiotherapy. For the whole series, 5-year event-free survival and overall survival were 58.8% and 79.4%, respectively. Outcome did not correlate with tumour site and size, but was strongly influenced by the feasibility of tumour complete resection. CONCLUSIONS This international study confirms the rarity of the disease, the critical role of surgical resection both as therapy and as a prognostic variable, and the potential efficacy of chemotherapy. The adoption of an intensive multidisciplinary approach is required, as well as the referral to highly experienced centres. Further international cooperation is needed to collect larger series and stimulate biological studies to improve our understanding of the biology and the natural history of PBL.

Mature and immature teratoma: A report from the second Italian pediatric study.

Teratomas demonstrate a benign clinical behavior, however they may recur with malignant components or as teratoma, and in a small group of patients prognosis could be fatal. After the first Italian study, we collected cases of teratoma, alongside the protocol for malignant germ cell tumors.

GATA-4 and FOG-2 Expression in Pediatric Ovarian Sex Cord-Stromal Tumors Replicates Embryonal Gonadal Phenotype: Results from the TREP Project

Aim GATA proteins are a family of zinc finger transcription factors regulating gene expression, differentiation and proliferation in various tissues. The expression of GATA-4 and FOG-2, one of its modulators, was studied in pediatric Sex Cord-Stromal tumors of the ovary, in order to evaluate their potential role as diagnostic markers and prognostic factors. Materials and Methods Clinical and histological data of 15 patients, enrolled into the TREP Project since 2000 were evaluated. When available, immunostaines for FOG-2, GATA-4, α-Inhibin, Vimentin and Pancytokeratin were also analyzed. Results In our series there were 6 Juvenile Granulosa Cell Tumors (JGCT), 6 Sertoli-Leydig Cell Tumors (SLCT), 1 Cellular Fibroma, 1 Theca Cell Tumor and 1 Stromal Sclerosing Tumor (SST). Thirteen patients obtained a complete remission (CR), 1 reached a second CR after the removal of a metachronous tumor and 1 died of disease. Inhibin was detectable in 11/15, Vimentin in 13/15, Pancytokeratin in 6/15, GATA-4 in 5/13 and FOG-2 in 11/15. FOG-2 was highly expressed in 5/6 JGCT, while GATA-4 was weakly detectable only in 1 of the cases. SLCT expressed diffusely FOG-2 (4/6) and GATA-4 (3/5). GATA-4 and FOG-2 were detected in fibroma and thecoma but not in the SST. Conclusions Pediatric granulosa tumors appear to express a FOG-2/GATA-4 phenotype in keeping with primordial ovarian follicles. High expression of GATA-4 does not correlate with aggressive behaviour as seen in adults, but it is probably involved in cell proliferation its absence can be associated with the better outcome of JGCT. SLCTs replicate the phenotype of Sertoli cells during embryogenesis in normal testis. In this group, the lack of expression of FOG-2 in tumors in advanced stages might reveal a hypothetical role in inhibiting GATA-4 cell proliferation pathway. In fibroma/thecoma group GATA-4 and FOG-2 point out the abnormal activation of GATA pathway and might be involved in the onset of these tumors.

Epithelial Tumors of the Ovary in Children and Teenagers: A Prospective Study from the Italian TREP Project

STUDY OBJECTIVE To report the clinical findings and treatment results of a series of patients with epithelial tumors of the ovary, registered and treated prospectively in a multi-institutional Italian network (TREP project) on rare tumors in children and adolescent between 2000 and 2014. DESIGN, SETTING, AND PARTICIPANTS Data on 16 patients, aged 22 to 206 months, from 7 centers were reviewed. All patients were grouped on the basis of the results of the first surgical approach, according to the Children Oncology Group staging system. RESULTS The most frequent symptom was abdominal pain; 3 patients were hospitalized for acute pain after ovarian torsion. Initial surgical treatment was complete in 15 of 16, and a biopsy was performed in 1 of 16. The histology examination revealed 8 benign tumors (7 mucinous cystadenomas and 1 serous cystadenoma) and 8 borderline tumors (2 serous and 6 mucinous). Fifteen of 16 patients maintained the complete remission after surgical treatment alone; 1 affected by Proteus syndrome died consequent to the progression of a synchronous Wilms tumor, after a delayed incomplete surgery. CONCLUSION Our analysis documented the rarity of these tumors in children and adolescents. No malignant histologies were found. Surgery alone was effective to cure the majority of patients. Considering the rarity of malignant entities, ovary-sparing surgery may be planned when an epithelial tumor is suspected on the basis of the preoperative work-up and intraoperative findings.

Clinical and pathologic considerations in a case of inflammatory myofibroblastic tumor of the spleen

Inflammatory myofibroblastic tumors, also called inflammatory pseudotumors, are rare pseudosarcomatous proliferations. Their behavior is generally not aggressive, but in most instances they can simulate malignant neoplasms, from which they are impossible to distinguish before excision. One case of myofibroblastic tumor of the spleen in a 5-year-old boy is described: the patient was treated with a partial splenectomy, which was found to be the best approach for diagnosis and treatment. The purpose of this report is to call attention to this entity with peculiar histologic and immunohistochemical characteristics, which has to be included in the differential diagnosis of splenic lesions and may be excised by a nonaggressive procedure.

Immunohistochemical expression of p16 in lipoblastomas

Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well-differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry. In this study, we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16. Moreover, p16 immunostaining was performed in 16 liposarcomas (11 WDL and 5 ML), 16 lipomas, and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children. Overall, p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas (10 WDL and 2 ML), with a sensitivity of 75%, a specificity of 90%, a positive predictive value of 80%, and a negative predictive value of 87%. All lipomas were p16 negative, whereas 5 liponecroses were positive. Accounting altogether the benign lesions versus liposarcomas, p16 showed a sensitivity of 75%, a specificity of 87%, a positive predictive value of 60%, and a negative predictive value of 93%. Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts, such as in adolescence or late recurrence. However, such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive.

Concurrent fibroadenoma and intraductal papilloma – A recurring complex lesion in a premenarcheal girl

Breast diseases are rare in childhood and adolescence, most lesions being fibroadenomas and papillomas. We report the case of an 11-year old girl with a complex breast lesion with hybrid features of fibroadenoma and intraductal papilloma with an early recurrence. Microscopically, the lesion was composed of dilated ducts showing intraluminal papillary projections with small to broad fibrovascular stalks. The typical leaf-like appearance of fibroadenoma was determined by the presence at the periphery of ducts compressed and distorted by the prominent stromal component. Despite its florid epithelial hyperplasia and mild cytological atypia (more evident in the relapse), immunohistochemical staining for p63 and smooth muscle actin highlighted a continuum outer myoepithelial layer, confirming the non-invasive appearance of the lesion. Two pathogenetic links have been hypothesized: one is based on the morphological continuum between these two entities, which may represent different evolutive stages in the same lesion; the other is based on epithelial/mesenchymal interactions. The possible malignant transformation of such complex lesion is also discussed, along with its differential diagnoses. The relevance of this case lies in its rarity, as well as in the therapeutic strategies related to its biological potential and to the necessity of a conservative treatment, due to the young age of the patient.

Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee

Introduction: From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma. Methods: Patients received two blocks of topotecan 2 mg/m2 on days 1, 2, and 3, and carboplatin 250 mg/m2 on days 4 and 5, followed by alternating blocks of topotecan–cyclophosphamide and carboplatin–etoposide for a total of six courses with 3-week intervals. Tumor response was assessed after two cycles, and local control was implemented when feasible. Results: A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan–carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively. Conclusion: the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan–carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.

Other Pulmonary Vascular Anomalies: Anatomy, Epidemiology, Diagnosis, and Treatment

Pulmonary vascular malformations consist of a spectrum of anomalies, ranging from abnormal vascular connection to normal lung tissue to vascular malformations that connect to abnormal lung tissue. These are rare lesions, the most common being bronchopulmonary sequestration, hybrid lesions containing both congenital cystic pulmonary airway malformation and bronchopulmonary sequestration features, lesions of aberrant venous or arterial systemic anastomoses and pulmonary arteriovenous malformations. Various classifications have been proposed using different terminologies, such as “congenital bronchopulmonary vascular malformation” and “congenital bronchopulmonary foregut malformation”; however, a proper classification is not defined yet, because none of the proposed theories is able to explain the origin of the various malformations, which share common elements. Only a multidisciplinary approach may allow a better understanding of their etiology, natural history, and associated anomalies, leading to the more appropriate treatment.Abstract Pulmonary vascular malformations consist of a spectrum of anomalies, ranging from abnormal vascular connection to normal lung tissue to vascular malformations that connect to abnormal lung tissue. These are rare lesions, the most common being bronchopulmonary sequestration, hybrid lesions containing both congenital cystic pulmonary airway malformation and bronchopulmonary sequestration features, lesions of aberrant venous or arterial systemic anastomoses and pulmonary arteriovenous malformations. Various classifications have been proposed using different terminologies, such as “congenital bronchopulmonary vascular malformation” and “congenital bronchopulmonary foregut malformation”; however, a proper classification is not defined yet, because none of the proposed theories is able to explain the origin of the various malformations, which share common elements. Only a multidisciplinary approach may allow a better understanding of their etiology, natural history, and associated anomalies, leading to the more appropriate treatment.