Jane Chatten

A review of 17 IV-S neuroblastoma patients at the children's hospital of Philadelphia

The records of 207 neuroblastoma patients seen at the Childrens Hospital of Philadelphia between 1944 and 1977 were reviewed to study some of the features associated with the unusually good prognosis found in patients with Stage IV‐S neuroblastoma. Initially, 22 patients appeared to fit the criteria of small primary tumor and distant disease in liver, skin, and/or marrow without evidence of bone metastases; 5 patients were subsequently rejected as being incorrectly staged. The remaining 17 patients had abdominal primary tumors and hepatic disease; in 12 of the 17, an enlarged liver was the presenting sign. Six patients had skin lesions, 4 had disease in the marrow on routine smear, and additional sites of spread were pancreas and bowel serosa. The treatment given was not systematic, and it was not possible to correlate any specific form of therapy with a satisfactory outcome. Eleven of 17 patients survived; 6 of 11 survivors had spontaneous regression of all or part of their disease, 5 of 6 who died received irradiation, chemotherapy, or both. Death usually occurred in the first month as a complication of the local disease; 1 patient succumbed to radiation nephritis. This study establishes that the special pattern of widespread neuroblastoma termed Stage IV‐S does exist, and that it is associated with a good prognosis. Careful consideration should be given before selecting treatment for the Stage IV‐S child because spontaneous regression is likely to occur in most of them. In patients with rapidly enlarging livers, renal or pulmonary complications may develop because of liver bulk or coagulopathies. Treatment should be directed to the liver in these cases because distant metastases seldom supervene. Low‐dose irradiation, mild chemotherapy, and possibly surgical release of intraabdominal pressure using a silastic patch have all been effective. Unfortunately, patients occasionally succumb to local disease in spite of these and more aggressive measures.

Prognostic signs in the surgical management of plexiform neurofibroma: The Children’s Hospital of Philadelphia experience, 1974-1994

OBJECTIVES To estimate the rate of progression of plexiform neurofibroma after surgery and to identify prognostic factors that predict progression. STUDY DESIGN A retrospective review of the inpatient and outpatient records of 121 patients, who had 302 procedures on 168 tumors over a 20-year period at a single large pediatric referral center. Data on age, location, indication for surgery, and extent of resection was analyzed for prognostic significance. RESULTS The overall freedom from progression was 54%. Children < 10 years old had a shorter interval of tumor control than older children (p = 0.0004). Tumors of the head/neck/face fared worse than tumors of the extremities (p = 0.0003). Less extensive resection predicted shorter interval to progression (p < 0.0001). Indication for surgery was not of prognostic importance. In multivariable analysis older age and location in the extremities were predictors of a better outcome. CONCLUSIONS Tumor progression is a serious problem for children with plexiform neurofibroma. Younger children, children with tumors of the head/neck/face, and tumors that cannot be nearly completely removed are at particular risk. These data may be useful in helping clinicians decide which patients and which tumors are most likely to benefit from surgical intervention.

Flow cytometric DNA analysis of neuroblastoma. Correlation with histology and clinical outcome

Clinical and histologic features of 38 cases of neuroblastoma were compared with data obtained by flow cytometric DNA analysis. Favorable clinical outcome was associated with an aneuploid stem line (P < 0.01) and a low percentage of tumor cells in the S, G2, and M phases of the cell cycle (P < 0.005). These favorable cytometric features were also associated with a favorable clinical stage (1, 2, 4s), and histologic evidence of Schwanns cell and ganglion cell differentiation. Consideration of cytometric data improved the sensitivity, specificity, and predictive efficiency of a current system for histologic grading of neuroblastoma.

Prognostic value of histopathology in advanced neuroblastoma: A report from the Childrens Cancer Study Group

We report the histopathologic findings in 420 patients with stage III and IV neuroblastoma enrolled in Childrens Cancer Study Group trials conducted from 1980 to 1983. A prospective study of individual cytohistologic features showed that outcome was related in a statistically significant manner to mitotic rate, multi-nuclearity, foam cells, ganglion cells, necrosis, and calcification, but only the latter was consistent for both stages. A similar test of four selected published classifications indicated the greatest prognostic value for the system developed by Shimada et al to distinguish favorable from unfavorable tumors. This classification proved significant in both stages and on examination of both primary and metastatic sites. Concordance in histologic assignment of prognosis by two observers was 83%. We conclude that the Shimada classification is valid and reproducible, and that it may be useful in planning therapy in advanced neuroblastoma. Selected cytohistologic parameters and the other classifications were less strongly predictive of outcome, but are worthy of continued study.

Ovarian Changes in Ataxia Telangiectasia

Ataxia telangiectasia is a well recognized syndrome involving several body systems [l, 5, 61. Recently, attention has been drawn t o the frequency of immunologic involvement in this disorder [lo]. The purpose of this report is to describe the occurrence of ovarian follicular agenesis in a child with ataxia telangiectasis and t o emphasize the frequency of ovarian abnormalities occurring in this syndrome.

Treatment of children with neurogenic sarcoma. Experience at the Children's Hospital of Philadelphia, 1958-1984.

Twenty‐four children aged 3 months to 18 years (median, 12 years) were treated for neurogenic sarcoma at the Childrens Hospital of Philadelphia Cancer Research Center from 1958 through 1984. Sixteen patients had neurofibromatosis (NF). The tumors arose in an extremity or in the trunk (15 patients), the retroperitoneum‐pelvis (6), or other sites (3). Twelve children underwent grossly complete excision of localized sarcoma; of them, five had no known residual tumor and seven had proven microscopic residual disease. Ten of the remaining 12 patients had grossly visible, residual localized disease, and two had lung metastases. After operation, nine were treated on a protocol with local radiation therapy (4000–6000 rad) plus vincristine, actinomycin D, and cyclophosphamide with or without Adriamycin (doxorubicin). The other 15 were treated variably. At 3 years, the proportion of tumor‐free survivors was 9 of 24 (37.5%). The significant favorable factors were the initial surgical removal of all gross tumor (9 of 12 with tumor excision were tumor‐free survivors at 3 years compared to none of 12 with gross residual sarcoma; P < 0.01), and a tumor mitotic rate under one per high‐power field. No significant correlation was found between tumor‐free survival expectancy and age, race, sex, the presence of NF, the site and size of the primary tumor, or use of the chemoradiotherapy regimen. More effective treatment programs are needed for children with neurogenic sarcoma, especially for those with unresectable tumors. Cancer 59:1–5, 1987.

Pulmonary vascular changes complicatingventriculovascular shunting for hydrocephalus

A patient is described in whom pulmonary hypertension and corpulmonale were noted 3 years after placement of a ventriculovascular shunting apparatus for treatment of hypdrocephalus. In addition, the histologic sections of lung tissue obtained from 65 patients with hydrocephalus who died at various intervals following placement of a ventriculovascular shunting apparatus were reviewed with regard to vascular alterations. A high incidence of “old” and “multiple” pulmonary vascular lesions was found in this group compared to the incidence in control subjects. This difference can be attributed to the operative procedure. The lesions in postmortem material were not widespread and did not suggest the diagnosis of pulmonary hypertension on purely histologic grounds.

Mesenchymal hamartoma of the liver in infants

Mesenchymal hamartoma of the liver is a rare benign tumor of childhood which has been confused with various other benign liver lesions, particularly vascular hamartomas which are mesodermal but not mesenchymal. The mass, frequently cystic, is characterized by an admixture of epithelial structures in a loose connective tissue stroma with fluid accumulation suggestive of lymphangiomatous channels. Four patients are presented and reviewed with 25 previously reported cases. The patients, usually asymptomatic, present during the first two years of life with progressive abdominal distention, which may be rapid because of increasing fluid content in the connective tissue stroma and cysts. Exploration and biopsy may be necessary before definitive excision. The present cases include a newborn, the youngest known, and a case in which radiation resulted in hyalinization of the mesenchyme, decrease in fluid content, and easlier resection. Respiratory distress and signs of vena caval obstruction due to intra‐abdominal pressure were noted. Prognosis after extirpation is very good. Cancer 42:2483–2489, 1978.

Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples.

Alveolar rhabdomyosarcoma is a pediatric soft-tissue tumor that is often difficult to distinguish from other small round-cell tumors. The PAX3-FKHR and PAX7-FKHR gene fusions that result from chromosomal translocations in this tumor provide potential molecular diagnostic markers. To apply these molecular markers to commonly available archival material, we used reverse transcriptase-polymerase chain reaction and oligonucleotide hybridization methodology to develop an assay capable of identifying PAX3-FKHR and PAX7-FKHR fusion transcripts in formalin-fixed, paraffin-embedded tissue. Use of a control assay for wild-type FKHR mRNA indicated that RNA was successfully isolated, reverse-transcribed, and amplified in 15 of 16 archival cases. Comparison of assay results for the PAX3-FKHR and PAX7-FKHR fusions with standard molecular assays of paired frozen material revealed that all eight cases of known fusion-positive rhabdomyosarcoma were correctly identified and distinguished as PAX3-FKHR or PAX7-FKHR. The seven cases of known fusion-negative rhabdomyosarcoma showed no evidence of either product. These results indicate that we have developed a molecular assay that accurately identifies the fusion transcripts characteristic of alveolar rhabdomyosarcoma in archival samples. This assay will be useful for diagnosis and for retrospective clinicopathologic correlative studies.

The role of surgery in localized neuroblastoma

A 30-year experience with 83 patients, median age two years, with Childrens Cancer Study Group (CCSG) Stages I, II, and III localized neuroblastoma was studied to determine factors that influence outcome. In addition, histology was reclassified in all patients based on the Shimada system, which is divided into five subtypes according to age and cytohistologic criteria. A multivariant survival analysis was carried out and patients were considered to have failed if they relapsed or died from any cause. Initial analysis determined that CCSG stage, Shimada histologic classification, and presence of disease in lymph nodes were statistically significant predictors of failure. Histology was the most important factor with Shimada subtypes 1, 2, and 4 having good outcome and 3 and 5 poor outcome. The latter three variables were combined to create four prognostic groups that had distinctly different rates of survival. Further analysis showed that after controlling for prognostic groups, extent of surgery was a statistically significant predictor. Patients who had more complete surgical resection had better disease-free survival.