Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation.

BACKGROUND: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. OBJECTIVE: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. METHODS: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. RESULTS: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). CONCLUSIONS: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry.

PURPOSE: We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry. PATIENTS AND METHODS: Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician. RESULTS: The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis. CONCLUSION: Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.

An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma.

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10-15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.

Adrenocortical tumors in children

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of Sao Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90 percent of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

Adrenocortical tumors in children.

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

Multifocal osteosarcoma following retinoblastoma.

Three survivors of retinoblastoma, one with hereditary bilateral and two with nonhereditary (spontaneous) unilateral disease, developed multifocal osteosarcoma. For one patient, unilateral retinoblastoma was followed by primitive neuroepithelioma at age 13 years. Multifocal chondroblastic osteosarcoma represented the patient's third malignant neoplasm. The course of multifocal osteosarcoma in these three patients compares to that of multifocal osteosarcoma which presents de novo in other patients without prior retinoblastoma.

Extensive genomic abnormalities in childhood medulloblastoma by comparative genomic hybridization.

We analyzed 27 samples of primary medulloblastoma, using comparative genomic hybridization and a novel statistical approach to evaluate chromosomal regions for significant gain or loss of genomic DNA. An array of nonrandom changes was found in most samples. Two discrete regions of high-level DNA amplification of chromosome bands 5p15.3 and 11q22.3 were observed in 3 of 27 tumors. Nonrandom genomic losses were most frequent in regions on chromosomes 10q (41% of samples), 11 (41%), 16q (37%), 17p (37%), and 8p (33%). Regions of DNA gain most often involved chromosomes 17q (48%) and 7 (44%). These findings suggest a greater degree of genomic imbalance in medulloblastoma than has been recognized previously and highlight chromosomal loci likely to contain oncogenes or tumor suppressor genes that may contribute to the molecular pathogenesis of this tumor.

Complications of pelvic exenteration in children who have genitourinary rhabdomyosarcoma.

BACKGROUND: Rhabdomyosarcoma is the most frequently encountered soft tissue sarcoma in children younger than 15 years of age. METHODS: The authors reviewed the early and long-term morbidity rate and clinical outcome of pelvic exenteration for genitourinary rhabdomyosarcoma (GU-RMS) in children. Of 43 patients with this diagnosis who were seen at St Jude Children's Research Hospital between 1963 and 1994, 17 underwent pelvic exenteration. These 13 boys and four girls ranged in age from 6 months to 15 years (median, 3.5 years). Their primary sites included prostate (n = 12), bladder (n = 4), and uterus (n = 1). All patients received multiagent chemotherapy and either preoperative or postoperative radiation therapy. Anterior exenteration was performed in 15 patients and total exenteration in two. The complications were classified as early or late (occurring within or after 30 days from the date of surgery) and as major or minor (depending on the risk of death or physical or functional disability). RESULTS: Thirteen of the 17 patients (76%) had 49 surgery-related complications. Wound infection (24%), fistula, abscess, and malnourishment (12% each) were the most common early major complications, with hydronephrosis (35%), bowel obstruction (24%), acute pyelonephritis, fistula, lymphedema, and ureter stenosis (12% each) making up the majority of late complications in this category. Relatively frequent minor complications included protracted paralytic ileus and hematuria (18%), cholelithiasis, chronic diarrhea and, peristoma skin irritation (12%). Disease-free survival was associated with the timing of surgery (P = .002). All but one of the 12 patients who underwent surgery within 6 months of diagnosis are alive, compared with only one of five whose surgery was performed after a longer interval. Pelvic exenteration for GU-RMS was associated with a high rate of serious complications in this series of patients treated over 31 years. CONCLUSION: With recent advances in surgical techniques, as well as improvements in preoperative and postoperative care, this procedure should continue to be applied in cases resistant to conventional therapy.

Outcome of treatment for pediatric sarcoma of the foot: a retrospective review over a 20-year period.

Soft tissue sarcomas (STS) arising in the foot are rare in children. From 1975 to 1994, 18 children (median age, 13.5 years) were treated at St Jude Children's Research Hospital for STS of the foot. Five children had rhabdomyosarcoma (RMS), with alveolar histology in four cases. All of these patients presented with metastatic disease, which proved fatal within 9 to 24 months despite combined modality treatment with chemotherapy, radiation, and surgery. Thirteen patients had nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). The most common histological variant was synovial sarcoma (7 patients). Of the 10 who presented with localized disease, seven survived 1 to 12 years (median, 7 years). Surgical treatment for these consisted of local excision (n = 2), wide local excision (n = 3), below knee amputation (n = 1 ), ray amputation (n = 1). Three received supplemental radiation, and one was also treated with chemotherapy. Local or distant recurrence proved fatal in the three other children who had localized disease. Three children who presented with metastatic NRSTS died 8 to 14 months after diagnosis. All surviving patients are without significant functional disability. In our experience, pediatric RMS of the foot has a poor outcome, attributable to both alveolar histology and presence of metastatic disease at diagnosis. In contrast, NRSTS of the foot is more often localized, and limited surgery with adjuvant radiation in the absence of clear margins should be the treatment of choice.

Soft tissue sarcoma of the hand in children: clinical outcome and management.

Soft tissue sarcomas (STS) of the hand are rare in children and adolescents. From 1965 through 1995, 18 children with STS of the hand were treated at our institution. Rhabdomyosarcoma (RMS) was diagnosed in 11 patients; alveolar histological results predominated (7 of 11 cases). Seven patients presented with metastatic disease and died 4 to 23 months (median, 9 months) from diagnosis; their surgical treatment comprised above-elbow amputation (n = 1), local excision (n = 1), and biopsy (n = 5). For the four patients who presented with localized RMS, surgery consisted of wide local excision (n = 1), local excision (n = 2), or ray amputation (n = 1). With an average follow-up of 5.5 years (range, 4 months to 18 years), 3 of the 11 patients diagnosed with RMS still survive (27%). The remaining seven patients presented with nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS); the most common histological variants were epithelioid and malignant fibrous histiocytoma (two cases each). Surgical treatment for these patients comprised ray amputation (n = 3), wide local excision (n = 3), excisional biopsy (n = 1), and regional lymph node dissection (n = 3). One patient received adjuvant multiagent chemotherapy; three patients received supplemental radiotherapy. Six of the seven (85%) patients are alive with no evidence of disease at an average follow-up of 4.7 years (range, 6 months to 12 years).

Clinical characteristics of small functioning adrenocortical tumors in children.

Twenty of 67 children registered on the International Registry of Childhood Adrenocortical Tumors between May 1988 and December 1994 had small adrenocortical tumors (defined for this study as measuring < or = 200 cm3 and/or weighing < or = 100 g). We reviewed the records of these 20 patients to characterize the clinical and pathologic findings and outcomes of children with small adrenocortical tumors. Median patient age was 2 years (range, 4 months to 5 years). There was only one boy. All had clinical signs of virilization, and seven had signs or symptoms of Cushing syndrome. A median 5.5 months (range, 1-40 months) had elapsed between the first signs of endocrine dysfunction and diagnosis. All tumors were surgically resected. Tumor volume was 3.3-195 cm3 (median, -8.7 cm3), and weight was 3.7-100 g (median, 36 gm Tumor samples were histologically reviewed in 18 cases. Eight were adenomas, and 10 were carcinomas (6 low grade and 4 high grade). Pathology records described tumor with diagnostic features of adrenocortical carcinoma in two patients. One patient received mitotane for 8 months after surgery. Only one patient had recurrent disease, which was detected 6 months after diagnosis and proved rapidly fatal. Another has been lost to follow-up. The remaining 18 patients are alive with no evidence of disease at a median 2.3 years (range, 6 months to 6.1 years) after diagnosis. Our data suggest that children with small adrenocortical tumors have an excellent prognosis with surgery as the sole therapy, regardless of tumor histiotype.

Epithelioid sarcoma in children.

Literature regarding the natural history and prognosis of epithelioid sarcoma in the pediatric population is sparse. During the past 11 years, eight patients with epithelioid sarcoma were treated at St Jude Children's Research Hospital. Of the eight children, six of whom were male, seven presented with localized disease and one with metastatic disease. The primary tumor was located in the upper extremity in four patients; the other sites were the scalp, external ear, back, and mediastinum. The mean duration of symptoms before diagnosis was 8.3 months (range, 1 to 12 months). Surgical treatment comprising amputation or wide local excision was performed in six patients, three of whom had additional lymph node dissection. Three patients received multiagent chemotherapy, and four patients were treated with supplementary radiation. Two patients died of progressive local and distant disease within 9 months of diagnosis. The other six patients are alive and have no evidence of disease 12 months to 10 years 6 months after the completion of treatment.