Neuroimaging of nevoid basal cell carcinoma syndrome (NBCCS) in children

Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant condition with a wide range of manifestations, including multiple basal cell carcinomas, medulloblastoma, odontogenic keratocysts (OKC) and skeletal abnormalities. Children with NBCCS also have a predisposition for secondary cancers after exposure to ionising radiation. In children undergoing imaging for posterior fossa mass and/or maxillofacial cysts, certain additional findings can raise the possibility of NBCCS. Making the diagnosis can significantly impact patient management, especially for children with medulloblastoma.     

Nevoid basal cell carcinoma syndrome with a unilateral giant ovarian fibroma in a Japanese 6-year-old girl

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by basal cell carcinoma, skeletal abnormalities, benign tumors including ovarian fibroma, and various other phenotypic expressions. Ovarian fibromas in NBCCS before puberty are very rare. We report a 6-year-old prepubescent girl with NBCCS showing skeletal abnormalities, medulloblastoma, and ovarian fibromas. The patient was referred to our hospital owing to abdominal distension. On admission, a huge elastic hard tumor was palpable and computed tomography showed a huge tumor of the left ovary. We performed a left salpingo-oophorectomy and diagnosed the tumor as a benign fibroma. Further examination of the computed tomography images showed skeletal abnormalities. In addition, the patient had a history of medulloblastoma at the age of 4 years. Therefore, we diagnosed NBCCS. A genetic examination indicated a novel 1 bp deletion in exon 18 (c.3055delG). Sequence analysis of exon 18 using DNA from the ovarian tumor revealed a mutant allele (c.3055delG) dominant to the wild-type allele, thus suggesting loss of heterozygosity in the PTCH1 gene, which is known to be associated with NBCCS. Conclusion On the basis of our experience, physicians treating pediatric ovarian tumors should be aware that such huge benign ovarian tumors may be a phenotype of NBCCS, as shown in our patient. In addition, genetic examination focusing on the PTCH1 gene might be important for diagnosis of NBCCS in pediatric patients.     

Radiation-sensitive genetically susceptible pediatric sub-populations

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation.     

Atypical teratoid/rhabdoid tumors of the central nervous system: clinical,radiographic and pathologic features

INTRODUCTION: Atypical teratoid/rhabdoid tumors (ATT/RT) of the central nervous system (CNS) are uncommon malignancies of childhood with an aggressive course and a uniformly fatal outcome. METHODS: The medical records, radiographic images and pathologic files at the Rainbow Babies and Childrens Hospital over the previous 6 years were retrospectively reviewed. RESULTS: Eight children underwent surgery for CNS ATT/RT at our institution since 1996. There were 6 boys and 2 girls. Median age at presentation was 21 months. Four tumors had multifocal disease at the time of diagnosis. Six patients received multiagent chemotherapy including 3 patients with autologous bone marrow transplantation, and 6 patients received radiation therapy. Median survival was 9 months from the time of diagnosis. CONCLUSIONS: In spite of aggressive therapy, the prognosis for ATT/RT remains dismal. The search for effective treatment strategies will require a better understanding of the biology and molecular genetics of this tumor.     

Second neoplasms in pediatric patients treated for cancer: a center's 30-year experience

To investigate the incidence and outcome of secondary neoplasms in pediatric patients treated for childhood cancer. Between December 1971 and January 2000, a total of 5859 patients younger than age 17 were diagnosed and treated for childhood cancers in our center. Of this group, 1511 (36%) patients were followed for more than 36 months. These long-term survivors were included in this analysis. Twenty-six patients developed a secondary malignancy with an overall risk of 1.7% in this cohort. The male:female ratio was 17:10, with a median age of 7.66 at diagnosis (range, 2 to 16 y). Four patients (14.8%) with Hodgkin lymphoma; 3 each (11.1%) with retinoblastoma and rhabdomyosarcoma; 2 each (7.4%) with Wilms tumor, Ewing sarcoma, medulloblastoma, ganglioneuroblastoma, and non-Hodgkin lymphoma; and 1 each (3.7%) with ependymoma, nasopharyngeal carcinoma, osteosarcoma, astrocytoma had a secondary malignant disease during the long-term follow-up period. Secondary malignant diseases were osteosarcoma in 6 patients, acute lymphoblastic leukemia in 2, acute myelogenous leukemia in 2, and rare malignant disease in others. Four patients with osteosarcoma developed disease within the radiation field. Osteosarcoma was the most frequently occurring secondary neoplasm. Less toxic treatment modalities should be used to decrease the risk of secondary malignant diseases.     

Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor

Second malignant neoplasms (SMN) in late childhood or young adulthood in individuals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of childhood cancer. Although radiation therapy is frequently implicated, chemotherapy with alkylating agents and antimetabolites has also been associated with SMN. Soft tissue sarcomas are among the most frequent primary malignancies complicated by a SMN and account for a majority of nonhematolymphoid SMN. We present the clinical and pathologic findings in a patient who had a peripheral neuroepithelioma (primitive neuroectodermal tumor, PNET) of the soft tissues diagnosed at 17 years of age, was treated with high-dose irradiation and multidrug chemotherapy, and developed an angiosarcoma 14 years later. This case represents an uncommon combination of mesenchymal malignancies in a young patient with an unusually favorable clinical course following the diagnosis of PNET. © 1992 Wiley-Liss, Inc.     

Long-term outcome of congenital cystic adenomatoid malformation

To determine the long-term outcome of congenital cystic adenomatoid malformation (CCAM), the records of all patients with CCAM treated in three Hungarian paediatric surgical centers between 1977 and 1996 were reviewed. Patients were followed for up to 20 years following diagnosis and treatment. In 20 patients CCAM was diagnosed postnatally and in 3 prenatally. Biodata including the operative procedures are presented. Follow-up findings between 18 months and 20 years after diagnosis showed better height and weight growth in patients operated upon in later childhood compared with those operated upon in infancy. The older the patient at the time of diagnosis, the better was the long-term outcome. Accepted: 5 January 1999     

Timing of radiation in children with medulloblastoma/PNET

BACKGROUND: To evaluate the importance of timing of radiation therapy in children with PNET/medulloblastoma, treated at the Brazilian National Cancer Institute (INCA). PROCEDURE: The records of 101 children with confirmed diagnosis of medulloblastoma were retrospectively reviewed. Patients had a median follow-up of 48 months (0.5-241 months). The age varied from 0.8 to 17.5 years (median: 7.6 years) and 21.7% were 3 years old or younger. RESULTS: According to the data collected from patients that received treatment for medulloblastoma from 1983 to 2001, the overall survival (OS) rate was 53% and the Disease Free Survival (DFS) rate was 40%. Multivariate analysis showed that under age 3 years, presence of neoplasic cells in the cerebrospinal fluid (CSF) at presentation or subtotal tumor resection resulted in a worse OS. The patients that received a biological effective dose (BED) greater than 44 Gy10 had better prognosis. Two-thirds of the patients had complete response after the initial treatment. Among them, 50% (34 patients) recurred, and of those 34 patients, 42% of them (14 patients) had recurrence in the posterior fossa. CONCLUSION: Surgery with total resection of the tumor and absence of neoplasic cells in the CSF are effective predictors of better OS. Radiotherapy was more effective when a BED was greater than 44 Gy10.     

Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor.

Second malignant neoplasms (SMN) in late childhood or young adulthood in individuals who have been successfully treated for an initial malignancy have emerged as a late effect of therapy in survivors of childhood cancer. Although radiation therapy is frequently implicated, chemotherapy with alkylating agents and antimetabolites has also been associated with SMN. Soft tissue sarcomas are among the most frequent primary malignancies complicated by a SMN and account for a majority of nonhematolymphoid SMN. We present the clinical and pathologic findings in a patient who had a peripheral neuroepithelioma (primitive neuroectodermal tumor, PNET) of the soft tissues diagnosed at 17 years of age, was treated with high-dose irradiation and multidrug chemotherapy, and developed an angiosarcoma 14 years later. This case represents an uncommon combination of mesenchymal malignancies in a young patient with an unusually favorable clinical course following the diagnosis of PNET.     

Secondary supratentorial anaplastic astrocytoma following treatment of medulloblastoma.

The development of secondary tumours is a rare but well known late effect of radiation therapy of lesions in the central nervous system. Most radiation-induced tumours are of mesenchymal origin, but on rare occasions gliomas can occur. We describe a patient in whom a supratentorial anaplastic astrocytoma developed 15 years after surgery and radiotherapy for a childhood posterior fossa medulloblastoma. A concise review of the pertinent literature is given.     

Abdominal malignant mesothelioma following autologous bone marrow transplantation: a case report

Secondary malignancies are a well-known late complication occurring in patients who undergo bone marrow transplant (BMT) during childhood. A boy with acute lymphoblastic leukemia experienced a BM relapse at the age of 14 years and underwent an autologous BMT conditioned with TBI and melphalan. Sixteen years later a malignant mesothelioma of the peritoneum was diagnosed. A surgical approach according to the Sugarbaker technique and hyperthermic peritoneal perfusion with CDDP and Adriamycin were performed. The patient is alive and well after a follow-up of 20 months. To the authors' knowledge this is the first case of mesothelioma as a secondary malignancy after BMT.     

Meduloblastoma: mejoría de la supervivencia en las últimas décadas. Experiencia de un centro

ObjectiveThe aim of the study is to analyse variations in the treatment of medulloblastoma, the most common childhood brain tumour, and its impact on survival over the past two decades, as well as its clinical and pathological features.Patients and methodsSurvival analysis of all patients under 14 years old diagnosed with medulloblastoma between January 1990 and December 2013 in a Paediatric Oncology Unit.ResultsSixty-three patients were diagnosed and treated for medulloblastoma, with a median follow-up of 5.1 years (range 0.65-21.7 years). The overall survival (OS) at 3 and 5 years was 66 ± 13% and 55 ± 14%, respectively.The OS at 5 years was 44% ± 25% in patients diagnosed in the 1990's, showing an increase to 70% ± 23% (p=0.032) since 2000. Clinical prognosis factors were included in the logistic regression model: age (p=0.008), presence of metastases and/or residual tumour (p=0.007), and receiving chemotherapy with radiotherapy after surgery (p=0.008). Statistically significant differences were observed for all of them.ConclusionIn our institution there has been a significant increase in medulloblastoma survival in the last decades. Multivariate analysis showed that this improvement was not related to the date of diagnosis, but with the introduction of chemotherapy in adjuvant treatment. This study confirmed that clinical factors significantly associated with worse outcome were age and presence of metastases at diagnosis.     

Abdominal Malignant Mesothelioma Following Autologous Bone Marrow Transplantation: A Case Report

Secondary malignancies are a well-known late complication occurring in patients who undergo bone marrow transplant (BMT) during childhood. A boy with acute lymphoblastic leukemia experienced a BM relapse at the age of 14 years and underwent an autologous BMT conditioned with TBI and melphalan. Sixteen years later a malignant mesothelioma of the peritoneum was diagnosed. A surgical approach according to the Sugarbaker technique and hyperthermic peritoneal perfusion with CDDP and Adriamycin were performed. The patient is alive and well after a follow-up of 20 months. To the authors' knowledge this is the first case of mesothelioma as a secondary malignancy after BMT.     

PART II. SURVIVAL AFTER RELAPSE DURING UNMAINTAINED REMISSION AND AFTER SECOND CESSATION OF THERAPY

Nygaard, R. and Moe, P. J. (Department of Paediatrics, University Hospital, Trondheim, Norway). Outcome after cessation of therapy in childhood leukemia. A population-based Nordic study of 986 patients. II. Survival after relapse during unmaintained remission and after second cessation of therapy. Acta Paediatr Scand Suppl 354: 20, 1989.
This is the second part of a population-based investigation of 986 patients after discontinuation of therapy for childhood leukemia. Patients who had their first relapse after cessation of therapy ( n =206) were studied for subsequent outcome in terms of survival after relapse. The patients with ALL ( n =191) were also analyzed according to patient variables with possible influence on survival. Fifty-one (26.7%) of the patients with relapse of ALL electively stopped therapy once more, and for them subsequent survival in remission was evaluated.
The overall estimated proportion alive at five years after relapse in unmaintained remission was 0.37 and at ten years 0.28. There was no significant difference in survival after relapse for males vs. females, and this could be attributed to the fact that isolated testicular relapses carried a better chance of subsequent survival than did relapses in other sites. Age at relapse did not have any influence on survival. However, time from cessation of therapy to first relapse was of prognostic value: Patients who relapsed within 6 months had a signifcantly lower survival than did those with relapse after longer periods in unmaintained remission.
Five-year DFS was 0.57 after second cessation of therapy in patients with ALL. Our study confirms that there may be more than one chance of cure.     

Secondary neoplasms after radiotherapy for a childhood solid tumor

This study was conducted to determine the outcome of patients who develop a second neoplasm after radiotherapy (RT) for a childhood solid tumor. From 1956 to 1998, 429 children with a malignant solid tumor were treated at a single radiation oncology facility. The medical records and radiotherapy charts were reviewed to determine if the patient developed a secondary neoplasm after treatment for malignancy. Twenty-three (5.4%) patients developed a second neoplasm. There were 12 males and 11 females with a median age at RT of 6.6 years (range, 2 months to 20 years). There were 14 malignant neoplasms in 13 (3.0%) and 14 benign neoplasms in 11 patients (2.6%). The types of initial solid tumors treated with RT were Ewing sarcoma in 6, Wilms tumor in 6, medulloblastoma in 5, neuroblastoma in 3, and other in 3. Median RT dose was 45 Gy (range, 12.3 to 60 Gy) using 4 MV in 9, 1.25 MV in 8, 250 KV in 4, and 6 MV photons in 1 patient. One child was treated using 15-MeV electrons. Fourteen had chemotherapy. Median follow-up was 23.2 years (range, 5.3 to 44.4 years). For the 14 malignant neoplasms, the median time interval from initial tumor to second malignancy was 10.1 years. The 14 second malignant neoplasms (SMN) were osteosarcoma in 3, breast carcinoma in 2, melanoma in 2, malignant fibrous his- tiocytoma in 1, dermatofibrosarcoma in 1, leiomyosarcoma in 1, mucoepidermoid carcinoma in 1, colon cancer in 1, chronic myelogenous leukemia in 1, and basal cell carcinoma in 1. Ten of the 14 SMN (71%) were at the edge or inside the RT field. The 5- and 10-year overall survival rate after diagnosis of an SMN was 69.2%; it was 70% for children with a SMN at the edge or inside the RT field and 66.7% for those outside of the RT field. The 14 benign neoplasms appeared at a median time of 16.9 years and included cervical intraepithelial neoplasia in 3, osteochondroma in 3, thyroid adenoma in 1, duodenal adenoma in 1, lipoma in 1, cherry angioma in 1, uterine leiomyoma in 1, ovarian cystadenofibroma in 1, and giant cell tumor in 1. Only 5 (36%) of the 14 benign tumors occurred in the RT field, with osteochondroma being the most common. Of 189 deaths occurring in 429 patients, only 3 (1.6%) were secondary to radiation-induced malignancy. Not all SMN in children receiving RT occur in the irradiated field. More than two-thirds of children with a radiation-induced malignancy are alive 10 years after the diagnosis of a SMN.     

Nasopharyngeal carcinoma in the pediatric age group: the northern Israel (Rambam) medical center experience, 1989-2004

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for less than 1% of all malignancies. Radiation therapy has been the mainstay of treatment of many years, but to improve survival, the use of chemotherapy has been advocated. This is a retrospective analysis of 13 patients less than 20 years of age treated for NPC the Rambam Medical Center during 1989 to 2004. Eight boys and five girls with a median age of 14.5 years (range 10-19) were included. Median follow up (including patients who died) was 6.15 years (range 1-15 years). Duration of symptoms was 1 to 24 months (median 5 months). Of the 13 patients, one patient had stage I, 6 had stage III, 5 had stage IV-A, and 1 had stage IV-B disease. Ten patients (77%) had undifferentiated carcinoma (WHO type III) and three patients (23%) had nonkeratinizing carcinoma (WHO type II). Most of the children received two or three courses of neoadjuvant multiagent chemotherapy consisting of cisplatin and 5-FU, followed by radiotherapy with doses in excess of 60 Gy. One child received concomitant chemoradiation. Ten of the 13 patients (77%) are alive without disease 6 years after diagnosis (range 1-15 years). One patient developed local and distant metastases 1 year after diagnosis and is currently receiving combined radiochemotherapy. Two patients died. Overall survival was 84%; event-free survival was 77%. Nine patients (69%) developed moderate to severe long-term complications. Pediatric NPC is curable by combined radiation and chemotherapy, with doses of radiation in excess of 60 Gy. Long-term follow-up is important for early detection of second malignancies as well as for radiation-induced endocrinologic deficiencies and other normal tissue complications.     

Survival and late effects on development of patients with infantile brain tumor

Background:  Most infants with brain tumor may have a poor prognosis. The aim of the present study was to retrospectively analyze the survival and outcome with regard to mental and physical development in 11 subjects with brain tumor; these tumors were diagnosed when the patients were under 1 year of age.
Methods:  The histological diagnoses of these tumors were astrocytoma, n  > 3; pineocytoma, n  > 2; teratoma, n  > 1; ependymoma, n  > 1; atypical teratoid/rhabdoid tumor, n  > 1; glioblastoma, n  > 1; medulloblastoma, n  > 1; and choroid plexus papilloma, n  > 1. Surgical resection was performed in eight patients, and adjuvant chemotherapy was administered to all except one patient with choroid plexus papilloma. Radiotherapy was additionally performed for four of the 10 chemotherapy patients.
Results:  Six patients survived. Among the surviving patients, five were under no treatment for 50–167 months after the diagnosis (median duration, 89 months), while one received chemotherapy for 20 months. Five patients exhibited mental retardation, and one patient experienced normal development after surgical removal of his choroid plexus papilloma. Diencephalic syndrome developed in one patient with pilomyxoid astrocytoma that necessitated hormone replacement therapy, and bodyweight over +2 SD was observed in two patients. The remaining five patients died 11–111 months after diagnosis (median duration, 24 months).
Conclusion:  The prognosis of infantile brain tumor with regard to mortality and developmental outcome remains poor. Furthermore, survivors require comprehensive medical and social support for an extended period.     

Leukemia in a Child with a History of Medulloblastoma

Leukemia of mixed lineage, was diagnosed in a 6.5-year-old boy with a history of medulloblastoma, 38 months after his initial cancer diagnosis. Therapy had included craniospinal radiation and nitrosourea-based chemotherapy. In addition, onset of leukemia was preceded by therapy with recombinant growth hormone for short stature. Although rare, leukemia is a treatment-related complication for patients with past brain tumors whose follow-up should therefore include surveillance with complete blood counts.     

Cyclophosphamide-based, seven-drug hybrid and low-dose involved field radiation for the treatment of childhood and adolescent Hodgkin disease

PURPOSE: The outlook for children and adolescents with Hodgkin disease (HD) is excellent with combined modality therapy. However, the long-term toxicities of multiagent therapy and radiation therapy remain of concern for these patients with curable disease. In an attempt to reduce long-term toxicities while preserving excellent cure rates, we developed a combined-modality protocol using a modified seven-drug hybrid and low-dose (2,000 cGy) involved field radiation therapy (RT). The hybrid used cumulative doses of alkylating agents and anthracyclines that were lower than those used in previous four-drug regimens and substituted a less leukemogenic agent, cyclophosphamide, for nitrogen mustard. PATIENTS AND METHODS: From 1991 through 1994 a cyclophosphamide, vincristine, procarbazine, and prednisone/adriamycin, bleomycin, and vinblastine hybrid was used to treat 29 patients with HD. Median age was 12 years (range 6-16 yrs). Patients who were postpubertal with early stage disease as determined by surgical staging were excluded. Treatment consisted of four cycles of therapy for stages I and IIA, six cycles for stages IIB and III, and eight cycles for stage IV. Twenty-two patients also received low-dose RT to areas of bulky disease. RESULTS: Twenty-eight patients (97%) had a complete response to chemotherapy. Five patients experienced relapse; two died from disease 27 and 29 months after initial diagnosis; three received additional therapy and are alive with no evidence of disease. Follow-up for all other patients is a median of 56 months (range 24-78 mos) from cessation of therapy and all have remained disease-free. At 5 years follow-up, actuarial disease-free survival is 82%, and the overall survival is 93%. There have been no clinically significant cardiac or pulmonary toxicities and no secondary malignancies. CONCLUSIONS: This therapy has resulted in 5-year overall survival and disease-free survival rates similar to regimens using higher doses of alkylating agents, anthracyclines, and radiation. Longer follow-up will be necessary to fully evaluate disease-free survival, organ damage, and quality of life.     

Pulmonary Langerhans cell histiocytosis: a variable disease in childhood

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is rare in childhood but occurs most commonly in children with multisystem (MS) LCH. In adults, by contrast, the lung is the most common and usually the sole organ affected. This retrospective study describes the clinical manifestation, course, and outcome of PLCH in children consecutively diagnosed at two Canadian institutions. PROCEDURE: The medical records of children (<18 years of age) consecutively diagnosed with LCH at the two institutions, were examined to ascertain the demographic details, pathological diagnosis, and organs involved. Further clinical details including, the clinical manifestation, details of therapy, course of lung disease, and clinical outcome were extracted for patients with PLCH. Initial and follow-up lung radiographs and CT scans were re-reviewed. RESULTS: Of the 178 patients with LCH, 40 (22.5%) presented with MS disease. Thirteen (7.3%) had PLCH, seven at initial diagnosis, and six at the time of disease progression. The median age was 10.1 months and mean was 11.9 months at diagnosis of PLCH. Lung involvement was always in the context of MS LCH, and half of the patients had no respiratory symptoms. Disease-free survival was around 70%, with a mean follow-up duration of 7 years. Of the four patients who died, three had other risk-organ involvement. Five of the nine surviving patients have had complete radiological resolution of PLCH. CONCLUSION: PLCH is seen in less than 10% of childhood LCH, but more than 30% of MS LCH. About half of children with PLCH may be asymptomatic, and the prognosis appears to depend on the presence or absence of other risk-organ involvement. The MS PLCH found in children appears to be a different disease from the single system (SS) PLCH seen in adults.