Stephen A. Heifetz

Complete Surgical Excision Is Effective Treatment for Children With Immature Teratomas With or Without Malignant Elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study

PURPOSE To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS Patients with immature teratomas treated at Pediatric Oncology Group or Childrens Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma.

Surgical resection alone is effective treatment for ovarian immature teratoma in children and adolescents: A report of the Pediatric Oncology Group and the Children’s Cancer Group☆☆☆★★★

OBJECTIVE In both adult women and children the potential for malignant recurrence from ovarian immature teratoma has prompted the standard use of chemotherapy after complete resection of the primary tumor. The efficacy of postoperative chemotherapy in children and adolescents with ovarian immature teratoma, however, has not been established. A pediatric intergroup trial (INT 0106) was designed to determine the need for postoperative chemotherapy in patients with ovarian immature teratoma after management with surgical resection only. STUDY DESIGN Between 1990 and 1995, 44 patients with completely resected ovarian immature tumor and without postoperative chemotherapy, who were able to undergo assessment, were accrued. Tumor tissue was evaluated by central pathology review to confirm diagnosis and determine tumor grading of immature neural elements. Patients were followed carefully for recurrence of disease with appropriate diagnostic imaging and serum marker studies. RESULTS Thirty-one patients had pure ovarian immature teratoma with a tumor grade of 1 (n = 17), 2 (n = 12), or 3 (n = 2). Age at diagnosis ranged between 1.5 and 15 years (median, 10). Of the 29 patients studied, the serum alpha-fetoprotein level was elevated in 10 (34%); the median level was 25 ng/ml. Thirteen patients had ovarian immature teratoma plus microscopic foci of yolk sac tumor. Tumor grade was 1, 2, or 3 in 1, 6, and 6 patients, respectively. Age ranged between 6 and 20 years (median, 12). In the 12 patients evaluated for serum alpha-fetoprotein, 10 (83%) had elevated levels; the median level was 262 ng/ml. The 4-year event-free and overall survival for the ovarian immature teratoma group and for the ovarian immature teratoma plus yolk sac tumor group was 97.7% (95% confidence interval, 84.9%-99.7%) and 100%, respectively. The only yolk sac tumor relapse occurred in a child with ovarian immature teratoma and yolk sac tumor who was then treated with chemotherapy and is alive and free of disease 57 months after recurrence. CONCLUSION The results of this study suggest that surgery alone is curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum alpha-fetoprotein or microscopic foci of yolk sac tumor are present. This experience strongly supports avoiding the long-term effects of chemotherapy in most children with ovarian immature teratoma by reserving postoperative therapy for cases with relapse.

Immature teratomas in children : Pathologic considerations a report from the combined Pediatric Oncology Group/Children's Cancer Group

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Childrens Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

The prepubertal testis (prenatal and postnatal): its relationship to intratubular germ cell neoplasia: a combined Pediatric Oncology Group and Children's Cancer Study Group.

Seminiferous tubules adjacent to germ cell tumors (GCT) in prepubertal boys frequently contain increased germ cells with abundant, clear cytoplasm. These cells are placental alkaline phosphatase (PLAP) negative and are usually not considered to represent intratubular germ cell neoplasia (ITGCN). A recent case report found p53 and proliferating cell nuclear antigen (PCNA) positivity in such cells and equated these PLAP-negative cells with ITGCN. Because the proto-oncogene c-kit is also a marker of ITGCN, immunohistochemical tests for c-kit and PLAP were performed on 28 testes adjacent to prepubertal GCT in children aged 2 to 45 months. Additional slides from testes not associated with GCT from 18 preterm infants and children ages 19 weeks to 7 years were also tested. An adult testis with seminoma and ITGCN served as a positive control. PCNA, PLAP, and p53 were tested on available slides. No intratubular germ cells adjacent to GCT in prepubertal children were positive for PLAP or c-kit; five of seven were positive for PCNA; p53 was present in the two examined. These results indicate that germ cells adjacent to infantile GCT are proliferative but not neoplastic and offer additional evidence that intratubular germ cells and GCT in prepubertal boys are different from those of adolescents and adults.

Anterior pericardial tracheoplasty for congenital tracheal stenosis: Intermediate to long-term outcomes

BACKGROUND Although several techniques for the treatment of long-segment stenosis of the trachea have been reported, including slide tracheoplasty, rib grafting, and use of a pericardial patch, the optimal repair remains controversial because of a lack of midterm to long-term follow-up data. METHODS To assess the intermediate and long-term outcomes of patients having repair with anterior pericardial tracheoplasty, we reviewed case histories of 12 patients (1984 to present). The median age was 6.7 months (range, 1 to 98 months), and the median weight was 6.0 kg (range, 0.97 to 42 kg). All patients underwent anterior pericardial tracheoplasty through a median sternotomy during partial normothermic cardiopulmonary bypass. An average of 13 tracheal rings (range, five to 23) were divided anteriorly, and a patch of fresh autologous pericardium was used to enlarge the trachea by 1.5 times the predicted diameter for patient age and weight. RESULTS There was one hospital death, and all but 2 patients are long-term survivors. All but 1 current survivor remain asymptomatic, with no bronchoscopic evidence of airway obstruction or granulation on the pericardial patch. All survivors examined have normal tracheal growth and development, with a median follow-up of 5.5 years (range, 1 to 11 years). CONCLUSIONS Anterior pericardial tracheoplasty for congenital tracheal stenosis provides excellent results at intermediate to long-term follow-up.

The Detection of Pulmonary Metastases by Helical Ct: A Clinicopathologic Study in Dogs

PURPOSE We sought to determine the accuracy of helical CT in the detection of pulmonary metastases. METHOD Four anesthetized dogs with metastatic osteosarcoma underwent helical CT with a collimation of 5 mm, a pitch of 2, and a reconstruction interval of 5 mm. All macroscopically evident metastases were recorded at autopsy. CT images were independently reviewed by 10 radiologists and compared with pathologic results. Alternate slices in the dog with the most metastases were microscopically examined in their entirety. RESULTS Pathologic examination of the lungs revealed 132 macroscopically evident pulmonary metastases, of which 74 (56%) were detected by at least one reader. Forty-four of the 99 (44%) metastases of < or = 5 mm in diameter were detected by at least one reader compared with 30 of 33 (91%) metastases of > 5 mm in diameter (p < 0.0001). The 10 readers reported a total of 107 false positives. Complete microscopy of alternate slices in the dog with the most metastases (n = 68) revealed an additional 38 micrometastases of < or = 3 mm in diameter. None of the 32 micrometastases of < or = 1 mm were detected by CT. CONCLUSION Helical CT has some limitations in the detection of pulmonary metastases.

Persistence of Barrett's esophagus in children after antireflux surgery: Influence on follow-up care

Adenocarcinoma arising in Barretts esophagus has recently been described in two children aged 11 and 14 years. The long-term follow-up of Barretts esophagus in children is not well described. We evaluated 16 cases of Barretts esophagus in children treated at this institution during the last 16 years. Ages ranged from 1.2 to 16 years (mean, 10.3 years). There were 11 boys and 5 girls. Barretts esophagus was documented by endoscopy in 14 instances and at autopsy in 2 patients with secretory diarrhea and tetralogy of Fallot who died of sepsis. Two children had cancer (neuroblastoma, leukemia) and died of their malignant disease. Five patients had cerebral palsy, 1 esophageal atresia, 1 Fanconis anemia, and 5 were otherwise normal children. Six were treated medically. Eight patients underwent Nissen fundoplication for complications of gastroesophageal reflux (GER). Five patients were available for follow-up endoscopy (mean, 2 years; range, 1.1 to 5.4 years). Endoscopy was performed on a yearly basis, obtaining biopsy specimens from multiple levels of the esophagus. Four children had satisfactory clinical response to an antireflux procedure including the resolution of a stricture in one case. However, in all 5 cases persistent metaplastic epithelium was documented and showed no evidence of regression. Although there has been speculation that Barretts esophagus in children may be more likely to revert to normal squamous epithelium than in the adult, there has been only one case of regression in 180 cases of Barretts esophagus occurring in children described in 37 reports in the literature.(ABSTRACT TRUNCATED AT 250 WORDS)

Urethral polyp presenting as interlabial mass in young girls

We describe two young girls who presented with an interlabial mass. Histologic examination of each excised mass revealed a benign urethral polyp covered with transitional and squamous epithelium. Urethral polyps should be included in the differential diagnosis of an interlabial mass in young female patients.

Hepatoblastoma: The Indiana Experience with Preoperative Chemotherapy for Inoperable Tumors; Clinicopathological Considerations

Analysis of the prognostic importance of various clinicopathological parameters in 17 hepatoblastomas (HBs) confirmed the utility of preoperative chemotherapy to convert inoperable to resectable tumors. There was no significant survival advantage for patients who underwent initial tumor resection compared with those resected following chemotherapy, although complete resection, with or without prior chemotherapy, was critical for cure. Young age was associated with better survival but did not correlate with histologic subtype or clinical stage. A relationship between low initial alpha-fetoprotein (AFP) level and tumor resectability was noted, perhaps related to tumor size, but tumor location was of greater importance than size in determining resectability. Neither the mean proportions of fetal and embryonal epithelium, nor their mitotic activity, nor the presence of vascular invasion in the prechemotherapy biopsy specimens was predictive of outcome, but the low mitotic activity of the fetal component correlated with ultimate resectability. On the other hand, although complete resection was necessary for survival, histologic examination of postchemotherapy specimens had additional predictive value; the presence of vascular invasion, the amount of viable mesenchyme, the extent of tumor necrosis, the proportion of embryonal epithelium, and the mitotic activity of the epithelial component in postchemotherapy resection specimens were each predictive of outcome. Although the presence of osteoid was not predictive, both the proportion of HBs that contained osteoid and the extent of mature mesenchymal tissues within individual HBs were increased by chemotherapy, suggesting that maturation of previously immature clones had been induced. We conclude that although complete resectability remains the fundamental goal of therapy, evaluation of the clinicopathologic characteristics that we have found to be predictive of outcome may permit tailoring of therapeutic regimens to individual patients; those whose tumors are deemed likely to respond well may require less toxic preoperative chemotherapy, and those deemed likely to progress in spite of complete resection may be considered for more aggressive postoperative regimens.

Necrotizing funisitis and herpes simplex infection of placental and decidual tissues: study of four cases.

Necrotizing funisitis (NF) is a macroscopically and microscopically distinctive pattern of umbilical cord inflammation recently heralded as presumptive of congenital syphilis. Four nonsyphilitic cases are presented in which herpes simplex virus (HSV) 2 antigen was demonstrated in the placenta by immunohistochemistry. The clinicopathologic findings in one case, including HSV 2 antigen in amniotic epithelium, subamniotic chorion, and Wharton jelly, indicate that NF was caused by chronic ascending primary HSV 2 infection, whereas those of the other three cases with HSV 2 Ag confined to decidual cell clusters suggest that NF was caused by chronic ascending bacterial infection and that latent endometrial HSV 2 infection was fortuitous. We conclude that (1) NF is caused by protracted inflammation of a structure whose normal anatomy precludes removal of inflammatory debris; (2) no single pathogen causes NF; and (3) NF is strongly associated with latent endometrial HSV 2 infection, which should be sought in all instances. Although latent HSV 2 endometrial infection may be more prevalent than currently recognized, we speculate that its strong association with NF may be more than causal; whereas the usual ascending bacterial infection leads to labor before NF has had sufficient time to develop, latent endometrial HSV 2 infection may alter local paracrine factors and delay parturition for the time sufficient to permit NF, a morphological hallmark of chronicity, to become apparent.