Paolo Tamaro

Renal Cell Carcinoma in Children: A Clinicopathologic Study

PURPOSE To identify the prognostic factors, treatment, and outcome of children affected by renal cell carcinoma (RCC). PATIENTS AND METHODS The series included 41 patients (18 males and 23 females) with a median age of 124 months observed at the 11 Italian Association for Pediatric Hematology and Oncology centers from January 1973 to January 2001. Clinical data, surgical notes, pathologic findings, and summaries of therapy were taken from the charts. RESULTS Seven (17%) of the 41 patients had a papillary histology, and 34 (82.4%) had nonpapillary histology. Eighteen patients (43.9%) had stage I, one patient (2.4%) had stage II, two patients (4.8%) had stage IIIA, 10 patients (24.3%) had stage IIIB, and nine patients (21.9%) had stage IV disease. One patient had a bilateral involvement at diagnosis. Seven patients experienced disease recurrence. Lung and liver were the most common distant lesions and usually were fatal. In this study, the major factor influencing the prognosis was the stage. Event-free survival at 20 years was 53.5% for all patients. Overall survival at 20 years was 54.9% for all patients. CONCLUSION RCC is a rare disease in children and adolescents. This neoplasm has a different clinical presentation in children compared with adults but the same outcome. In our experience, patients with localized disease could be cured by nephrectomy alone. Prospective studies in a larger number of patients are needed to confirm radiation therapy and biologic response modifiers as effective adjunct therapy in RCC stage III. The alternative therapy seems warranted in patients with advanced disease.

Features and outcome of neuroblastoma detected before birth

BACKGROUND/PURPOSE The growing use of routine ultrasonography during pregnancy is leading to an increasing number of prenatally diagnosed neuroblastomas. Optimal strategy has not yet been defined for these patients, because knowledge on this particular neuroblastoma (NB) population is still limited. However, definite guidelines are needed to avoid inadequate treatment. The authors analyzed the cases of antenatally detected NB (ADNB) reported in the Italian Neuroblastoma Registry during the past 6 years to elucidate the features of this subset of NB. METHODS The Italian Neuroblastoma Registry was reviewed for the period January 1993 to December 1998 to collect clinical, radiographic, surgical, and histopathological data on ADNB cases. NB stage was evaluated according to INSS criteria. All patients had undergone imaging (computed tomography or magnetic resonance imaging) of the primary tumor and bone marrow biopsy before surgical resection. RESULTS Seventeen patients were identified. Primary tumour site was adrenal glands in 16 cases and retroperitoneal ganglia in 1. Stage distribution was stage I, 13 cases; stage II-A, 1 case; stage II-B, 1 case; stage IV-S, 2 cases. All cases underwent primary tumour resection. Mean age at surgery was 4 weeks. Resection of primary tumor was radical in 16 cases, partial in 1. All tumors were characterised by favourable histology according to Shimada classification. N-myc gene amplification was studied in 14 patients. N-myc amplification was detected only in a newborn with stage II-A NB, who died of massive bleeding 2 days after tumor resection. DNA index and 1p deletion were studied in 11 and 8 patients, respectively. Both diploidy and deletion of 1p were observed in a newborn who subsequently died of disease progression despite surgery, chemotherapy, and radiation therapy. Fourteen of 17 patients currently are alive and free of disease, and one with IV-S NB and short follow-up is alive with disease. CONCLUSIONS Our data give evidence that in most cases infants with ADNB represent a subset of patients with excellent outcome. Aggressive treatment may not always be necessary. Infants with ADNB with unfavorable features should undergo early surgical excision, whereas patients with favourable features could be observed awaiting spontaneous regression of the mass, reserving delayed surgery for tumors that increase in size or do not regress.

Histopathologic, immunophenotypic, and genotypic analysis of Ki‐1 anaplastic large cell lymphomas that express histiocyte‐associated antigens

CD30/Ki‐1 antigen expression in 243 cases of malignant lymphomas was examined using Ber‐H2 monoclonal antibody. Among them 20 cases were categorized as Ki‐1 anaplastic large cell lymphoma. in two of these cases histiocyte‐associated markers were also expressed. in these cases histopathologic and extensive in situ immunophenotypic analyses were used with genotypic studies in the determination of cell lineage. A sinusoid histologic pattern of involvement with partial lymph node infiltration by pleomorphic neoplastic cells was noticed in the nodes from both patients. Solid areas of node replacement resembling metastatic carcinoma were seen in Patient 1. Immunohistologically, tumor cells of both cases were positive for CD30, CD25, CD71, LN3 (HLA‐DR), EMA, CD45, CD74, vimentin, alpha‐1‐antichymotrypsin, and CD68. Patient 1 was also CD45RO+, CD43+, whereas Patient 2 was positive for alpha‐1‐antitrypsin and CD4 tumor cells. Genotypic studies revealed that TCRβ and TCRγ chain genes were clonally rearranged in Patient 1, whereas no rearrangements were detected in Patient 2. This study supports the view that some Ki‐1 anaplastic large cell lymphomas may express multiple histiocyte‐associated antigens and confirms that this group of neoplasms have immunophenotypic heterogeneity. the results of genotypic analyses used with immunophenotyping does not exclude that the tumor cells in these cases may be of true histiocytic origin despite the Ki‐1‐positive phenotype.

Avascular necrosis of bone in children undergoing allogeneic bone marrow transplantation

Avascular necrosis of bone (AVNB) is reported in two children after allogeneic bone marrow transplantation. Preparation therapy for transplantation included cyclophosphamide and total body irradiation. Corticosteroids, cyclosporine A, and methotrexate were used for graft‐versus‐host‐disease prophylaxis. The possible role of combination therapy in development of AVNB is discussed, but a direct relationship with single agents was not found. However, an early diagnosis is important to institute conservative treatment and prevent irreversible damage to affected joints. Magnetic resonance imaging was found to be more sensitive than plain radiography in early detection of AVNB.

Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study

The outcome of high-risk (HR) acute lymphoblastic leukemia patients enrolled in the AIEOP-BFM ALL 2000 study in Italy is described. HR criteria were minimal residual disease (MRD) levels ≥10(-3) at day 78 (MRD-HR), no complete remission (CR) at day 33, t(4;11) translocation, and prednisone poor response (PPR). Treatment (2 years) included protocol I, 3 polychemotherapy blocks, delayed intensification (protocol IIx2 or IIIx3), cranial radiotherapy, and maintenance. A total of 312 HR patients had a 5-year event-free survival (EFS) of 58.9% (standard error [SE] = 2.8) and an overall survival of 68.9% (SE = 2.6). In hierarchical order, EFS was 45.9% (4.4) in 132 MRD-HR patients, 41.2% (11.9) in 17 patients with no CR at day 33, 36.4% (14.5) in 11 patients with t(4;11), and 74.0% (3.6) in 152 HR patients only for PPR. No statistically significant difference was found for disease-free survival in patients with very HR features [MRD-HR, no CR at day 33, t(4;11) translocation], given hematopoietic stem cell transplantation (HSCT) (n = 66) or chemotherapy only (n = 88), after adjusting for waiting time to HSCT (5.7 months). Patients at HR only for PPR have a favorable outcome. MRD-HR is associated with poor outcome despite intensive treatment and/or HSCT and may qualify for innovative therapies. The study was registered at www.clinicaltrials.gov as #NCT00613457.

Undifferentiated (embryonal) sarcoma of the liver in childhood: results of a retrospective Italian study.

The clinical features and the treatment of undifferentiated (embryonal) sarcoma of the liver in 8 patients younger than 19 years old were analyzed. AH these cases were registered in the retrospective multicentric study on childhood malignant tumors of the liver, conducted between 1983 and 1985 by the Italian Association of Pediatric Hematology Oncology. The age of the patients ranged from 94 to 190 months (median = 113.5 months); all children were males. An abdominal mass was the common presenting features. Abnormalities in hemogram and common liver tests were rarely reported. Angiography revealed various degrees of vascularization in these tumors. Two patients achieved a surgical complete remission (CR) at diagnosis; one patient achieved surgical CR after primary chemotherapy with vincristine, adriamycin, cyclophosphamide and 5-fluorouracil, which reduced the tumor volume and permitted surgical resection. Two of these patients are still in CR at 14 and 60 months after diagnosis; the third patient died of liver failure without evidence of recurrence 6 months after diagnosis. All of the other patients, who never achieved CR, died of disease. One was lost to follow-up, and one surgical death occurred. Reports of childhood undifferentiated sarcoma are reviewed.

Survival after relapse in children with solid tumors: A follow-up study from the Italian off-therapy registry†

Despite the increased survival of children with solid tumors, a significantproportion of cases still relapse following treatment discontinuation, and knowledge about the long‐term outcome of this selected group of patients remains incomplete.

Randomized Multicentric Italian Study on two Treatment Regimens for Marrow Relapse in Childhood Acute Lymphoblastic Leukemia

This paper reports the results of a multicentric randomized clinical trial on the treatment of first hematological relapse in childhood ALL. Induction treatment consisted of vincristine, adriamycin, L-asparaginase, and prednisone. Patients achieving complete remission were randomized to two maintenance regimens (A and B). Regimen A consisted of five different drug associations including VM26 and IDMTX in a sequential schedule; Regimen B was essentially classical Spiers schedule for the first year, followed by a milder treatment. Eighty-four of 102 evaluable patients (82%) achieved second complete remission. The two maintenance regimens were similar as regards duration of second complete remission (median duration A, 32 weeks; B, 37 weeks) and toxicity. Better results were obtained in patients relapsing after 12 months from suspension of treatment in first complete remission than in those relapsing within the first year off therapy (82.8% vs. 31.4%). In group A fewer CNS relapses were reported. The two regimens produced results similar to those reported by other authors. The good prognosis in patients relapsing at least 1 year after treatment suspension in first complete remission must be emphasized.

Late deaths and second primary malignancies among long-term survivors of childhood cancer: An Italian multicentre study

A multicentre registry of children who had been successfully removed from therapy for some common childhood cancers (Hodgkins disease, non-Hodgkins lymphoma, neuroblastoma, nephroblastoma, acute lymphatic leukaemia and other leukaemias) was established in Italy in 1981. The present study describes mortality and occurrence of second primary malignancies (SPMs) among 1467 children who were alive when the registry was established. Follow-up ended on December 31, 1983 for mortality and 1 year later for the occurrence of SPMs. Sixty-seven deaths were recorded, 11 of which were due to causes other than progression of the original disease. Eleven incident SPMs were identified (i.e. 3 acute myeloid leukaemias, 3 thyroid carcinomas, 1 bilateral breast carcinoma, 1 liver malignant mesenchymoma, 1 astrocytoma, 1 chondrosarcoma and 1 osteosarcoma) corresponding to an incidence rate of 2.1/1000 patient-years at risk. Anecdotal reports were collected regarding 2 further SPMs (a thyroid carcinoma and a myeloid leukaemia) as well as several benign tumours, including 2 mammary fibroadenomas.

Effect of peptichemio in nonlocalized neuroblastoma.

PTC, a mixture of oligopeptides of m‐L‐sarcholysin, acting primarily as an alkylating agent, was utilized as initial therapy following diagnosis in 80 children with nonlocalized neuroblastoma. Of the 67 evaluable patients (21 Stage III, 41 Stage IV and five Stage IV‐S), 51 had measurable lesions allowing to evaluate PTC activity; objective tumor responses to the drug were recorded in 45 of these 51 cases (88.2%): 5/5 Stage III, 37/41 Stage IV, 3/5 Stage IV‐S. Complete responses were obtained in seven patients (13.7%), partial responses in 32 (62.7%), objective improvement in six (11.8%). Four patients (7.8%) had either no tumor change, or tumor progression. There have been two early drug‐related deaths (3.9%). Stage III and IV patients responding to PTC were then treated by irradiation + VCR, followed by cycle of a combination of Adriamycin, vincristine, and cyclophosphamide. Stage IV‐S patients received no further therapy. Thirteen of 21 Stage III (61.9%), five of 41 Stage IV (12.2%) and four of five Stage IV‐S (80%) are presently alive from 19–48 months (median, 27 months). PTC is an effective agent in advanced neuroblastoma. However, the results of this report do not indicate that its addition to a “standard” treatment, at least in the schedule adopted in this protocol, has improved the final outcome of children with nonlocalized disease.