Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.

Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-ß as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4 Gy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.

The Gist of literature on pediatric GIST: review of clinical presentation.

AIM/BACKGROUND: To provide a review of existing literature on pediatric GIST with focus on clinical presentation. METHODS: A MEDLINE search was conducted in July 2007 to give an overview on literature concerning pediatric gastrointestinal stromal tumors (GISTs) with a focus on clinical presentation, using keywords "gastrointestinal stromal tumor" and one of the following "young/boy/girl/child/children/pediatric." Two of the authors sorted the resulting abstracts by relevance for a review on clinical aspects of pediatric GIST if they were in English language, not explicitly only reporting of adults and describing clinical features of patients. RESULTS: One hundred and six articles were found, 43 of which were excluded because they did not match the criteria mentioned above. We found 97 patients in the articles meeting our criteria, of which 38 cases had to be excluded, because of lacking clinical data, negative staining for CD117 or syndromal occurrence. This left 59 patients for analysis of clinical symptoms in the presentation of nonsyndromal CD117-positive GIST in children. DISCUSSION: Clinical feature most frequent was anemia in 86.4% (n=51) symptomatic either through acute or subacute bleeding. There was no palpable tumor in 88.1% (n=52), no abdominal pain in 84.7% (n=50), and no vomiting in 88.1% (n=52). Girls tend to show more high-grade tumors and existing case reports show a 2.7-fold higher incidence in females. Altogether epithelioid cell tumors are most frequent, although in boys spindle-cell tumors are reported more often. On the basis of National Institute of Health criteria (6) tumors were low grade in 22% (n=13), medium grade in 37.3% (n=22), and high grade in 35.6% (n=21). There were more high-grade tumors in girls than in boys (40.5% vs. 28.6%). Local excision was the operation most often performed, but details of surgery were missing in most cases. CONCLUSIONS: Pediatric GIST is a rare but considerable diagnosis in chronic anemia, which is the most frequent clinical finding with this tumor entity. Recent review articles focus on histopathologic criteria but omit clinical features and course of disease. In nonsyndromal CD117-positive GIST, girls tend to show more high-grade tumors and existing literature on pediatric GIST shows a 2.7-fold higher incidence in females. Altogether epithelioid cell tumors are most frequent, although in boys spindle-cell tumors are reported more often. Together with known differences in molecular changes and local as well as systemic tumor behavior this strongly suggests that pediatric GIST represents a different entity than adult GIST. After establishment of clear-cut pathologic features in the past, reports on preoperative diagnostic findings, long-term follow-up, and therapy have to be emphasized to clarify the relationship of these entities.

Haematopoietic stem cell transplantation for amegakaryocytic thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAT), a rare syndrome with failure of megakaryopoiesis, cannot be cured by immunoglobulins, steroids or cyclosporin, but only by allogeneic bone marrow transplantation (BMT). We report on eight patients with CAT, all of whom were dependent at the time of BMT on platelet transfusion. Sources of haematopoietic progenitor cells were bone marrow (n = 5), peripheral stem cells (n = 2) and cord blood (n = 1). Seven patients engrafted. Both patients with matched unrelated donor transplants died, six patients are well with stable platelet counts 3-27 months after transplantation. BMT represents a curative option for CAT. The benefit of using alternative marrow donors should be carefully evaluated.

Nasopharyngeal carcinoma in childhood and adolescence: concept and preliminary results of the cooperative GPOH study NPC-91. Gesellschaft für Pädiatrische Onkologie und Hämatologie.

BACKGROUND: The increasing use of chemotherapy has improved the prognosis of patients with nasopharyngeal carcinoma (NPC), and the authors demonstrated the beneficial effect of adjuvant interferon (IFN)-beta in a previous pilot study of children with advanced stage NPC. The current multi-institutional, cooperative GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie) study NPC-91 was begun in 1992 to determine the efficacy of preradiation chemotherapy, radiotherapy, and adjuvant IFN-beta, in the treatment of advanced stage NPC. METHODS: Of a total of 22 patients, 21 had American Joint Committee on Cancer Stage III or IV disease, and 1 had Stage II disease. The median age was 12 years (range, 8-16 years). Twenty of 22 received 3 courses of preradiation chemotherapy consisting of methotrexate 120 mg/m2 on Day 1, cisplatin 100 mg/m2 on Day 1, and 5-fluorouracil 1000 mg/m2 for five days as well as 6 doses of leucovorin 25 mg/m2 every six hours beginning on Day 2. The Stage II patient received no chemotherapy, and chemotherapy was terminated for another during the first course. All patients had radiation therapy, stratified by stage. The cumulative dose to the primary sites was 59.4 gray (Gy), with single doses of 1.8 Gy. A total of 45 Gy was delivered to the neck area. Finally, all patients were treated with recombinant IFN-beta (10(5) U per kg of body weight) 3 times a week for 6 months. RESULTS: The response rate was 91%. These patients stayed in first remission during a median follow-up of 32 months. With the exception of one reversible cardiotoxicity, moderate chemotherapy-related toxicity was observed. CONCLUSIONS: In this study, patients with advanced stage NPC had a good prognosis with treatment consisting of neoadjuvant cisplatin and 5-fluorouracil, radiotherapy, and adjuvant IFN-beta. It is particularly noteworthy that distant metastases did not develop.

Herpes virus (KSHV) associated Kaposi sarcoma in a 3-year-old child with non-HIV-induced immunodeficiency.

UNLABELLED: A 3-year-old boy of German descent suffered from two episodes of Streptococcus pneumoniae meningitis within 2 months. One month previously, the first skin lesion of Kaposi sarcoma (KS) had been observed behind his right ear. During the following 2 years KS disseminated not only mucocutaneously but also to visceral organs. Immunological evaluation revealed severe lymphocytopenia with reduced helper/suppressor T-cell ratio and impaired humoral immune response to pneumococci. Extensive laboratory tests gave no evidence for known immunocompromising infections. However, recently described DNA sequences from a Kaposi sarcoma-associated herpesvirus (KSHV) could be identified within skin tissue. As chemotherapy failed to stop tumour progression the patient was referred for bone marrow transplantation. Eighteen months later the KS is in remission and the patient in a good general condition. CONCLUSION: The case supports the hypothesis that KSHV is involved in the aetiology of KS. Bone marrow transplantation is possibly a therapeutic option for KS in patients with immunodeficiency not related to human immunodeficiency virus infection.

[SCE rate and lymphocyte differentiation in children with acute lymphoblastic leukemia and SCE rates of leukemia patients in long-term remission]. / SCE-Rate und Lymphozytendifferenzierung bei Kindern mit akuter lymphatischer Leukämie sowie SCE-Raten von Leukämiepatienten in Langzeitremission.

Sister chromatid exchanges (SCE) and lymphocyte subsets of children with acute lymphoblastic leukemia (ALL) were investigated in children with ALL during chemotherapy and at least 5 years after chemotherapy. The treatment of the new admitted patients followed protocol ALL-BFM-90. Children with ALL at the time of diagnosis showed statistically significant higher SCE frequencies (4.9 +/- 0.77) than healthy controls (3.6 +/- 0.93; p = 0.002). The in vivo effects of cyclophosphamide (CP) resulted in a dramatic increase of the SCE frequency (20.5 +/- 3.76). This increased SCE level of lymphocytes might reflect an instability of DNA or a deficiency of DNA repair capacity. However, immediately one week after the administration of CP, the SCE rate decreased. This decline of SCE frequency correlates with a severe reduction of the absolute numbers of T lymphocytes. The observed reduction of SCE frequency may be due to a depletion of T lymphocytes, or a repair of DNA. The patients in long term remission ( > 5 years) have had the therapy according BFM-83 (9 pat.) and modified 'Pinkel-regime' (2 pat.). No difference was found between the SCE-rate of the patients in remission and of the age-dependent control group. These results might correlate with the low risk for future development of relaps or second malignancy.

[Combined treatment of nasopharyngeal cancer in children and adolescents--concept of a study]. / Kombinierte Behandlung des Nasopharynxkarzinoms bei Kindern und Jugendlichen--Konzept einer Studie.

Nasopharyngeal carcinomas (NPCs) are malignant tumors which exhibit a wide disparity in their age, racial, and geographic incidence. In parts of Africa NPCs account for 10% to 20% of childhood malignancies. In USA and Europe, the NCP is an uncommon tumor (0.2% of all malignancies) and amounts to only 1% to 2% of childhood malignancies. Etiology and pathogenesis are closely related to an infection with Epstein-Barr Virus (EBV) and the EBV genome was detected in tumor tissues. Children with NPC differ from their adult counterparts in having a closer association with Epstein-Barr-Virus-Infections. The classical lymphoepithelial carcinomas (Cologne type II-type III) have been found in young patients. Clinically, the disease is aggressive, characterised by frequent metastases in bone and lung. These carcinomas are associated with significantly elevated anti-EBV-titers. The prognosis of children with advanced NPC is poor with a 5-year survival rate between 20-30%. Radiotherapy is the treatment of choice in NPC which has provided an improvement in local tumor control in recent years. Human fibroblast interferon is an active agent in recurrent NPC. Seven children have been treated with IFN-beta, (6 with human und 1 with recombinant IFN-beta) as an adjuvant therapy in doses of 10(5) U/kg body weight three times a week for half a year. All patients received radiotherapy to primary site and had advanced stages (III-IV) at presentation. The patients' age ranged from 14-19 years at diagnosis. Six are still in CR (RFS are 10, 8, 8, 7, 6 and 1.5 years) and one patient relapsed after 18 months.(ABSTRACT TRUNCATED AT 250 WORDS)