Inci Ayan

Childhood nasopharyngeal carcinoma: from biology to treatment

Nasopharyngeal carcinoma is a rare disease in children with distinct epidemiological, histopathological, and clinical characteristics. Incidence varies widely around the world but bimodal incidence graphs show that in some populations a disproporionate number of cases occur in late childhood. Children with nasopharyngeal carcinoma almost always have the undifferentiated variant of the disease, which is associated with advanced locoregional spread and distant metastases. Both genetic and environmental factors contribute to the development of nasopharyngeal carcinoma, as evidenced by its risk factors which include: specific HLA subtypes; deletions of chromosomes 3p, 9p, 11q, 13q, and 14q; mutations of p53 and RB2/p130; polymorphism of the CYP2E1; and infection with Epstein-Barr virus. Traditional treatment consists of high-dose radiotherapy and cure rates range between 30% and 60%. The high incidence of failure due to systemic disease in children means that chemotherapy is preferable for first-line treatment in advanced-stage disease. Currently, cisplatin-based induction or adjuvant chemotherapy combinations are used along with high-dose radiotherapy. Although combined modality treatment has increased 5-year survival to 70-90%, late morbidity is a major concern.

Brain metastasis in pediatric extracranial solid tumors: survey and literature review

Objectives: Brain is a rare site of metastasis in most extracranial pediatric solid tumors. The aim of this study is to investigate the incidence, treatment, prognosis of brain metastasis in extracranial pediatric malignant tumors in a single institution and to review the literature.Methods: From September 1989 to December 2002, 1100 children ≤16 years of age with extracranial solid tumors including lymphomas were diagnosed and treated in the Division of Pediatric Oncology, Oncology Institute, Istanbul University. Patients with parenchymal metastases in the brain were assessed.Results: Sixteen (10 female, 6 male) of 1100 patients (1.45%) with extracranial solid tumors developed brain metastases. The median age of the patients was 10.5 (1–16) years. The diagnosis was sarcomas in 12 patients: 5 osteosarcomas, 4 Ewing’s sarcoma family tumors, 1 rhabdomyosarcoma, 1 clear cell sarcoma of the soft tissue, 1 alveolar soft part sarcoma. Two patients had Wilms’ tumor and two had germ cell tumors. Four patients (25%) had brain metastasis at diagnosis. Twelve (75%) developed brain metastasis during therapy or relapse at a median duration of 16 (1–70) months from initial diagnosis. All patients had metastases to various sites, mostly lung, at the time the brain metastases were detected. Treatment included surgery, followed by postoperative radiotherapy (RT) and chemotherapy (CT) in 1, S and RT in 1, S in 1, RT and CT in 6, RT in 1, CT in 1 and no treatment in 5. Only one patient with alveolar soft part sarcoma is alive with disease 20 months from diagnosis of brain metastasis. All other patients died at a median time of 2 months (2 days–6 months) from the time of brain metastasis.Conclusions: Children with metastatic cancer who develop headaches or any other neurologic symptom should be investigated for possible brain metastasis. Although, the outcome for these patients is dismal in this series and in the literature; reports of long term survival in a few cases with Wilms’ tumor, osteosarcoma and alveolar soft part sarcoma who had isolated brain metastasis, suggest that a subset of patients may benefit from therapy.

Ependymal tumors in childhood

Ependymal tumors are classified as ependymoma (benign or low grade) versus anaplastic ependymoma (malignant or high grade). Ependymomas represent 5–10% of intracranial neoplasm in children. In this study, demographic data and the treatment results of pediatric patients with ependymal tumors, treated in a single institute, is reported.

Yolk sac tumours of the ovary: Evaluation of clinicopathological features and prognostic factors

OBJECTIVE To evaluate the clinicopathological prognostic features, factors and outcomes of chemotherapy in ovarian yolk sac tumours (YST). STUDY DESIGN We reviewed the medical records of 32 women with ovarian YST treated from 1990 to 2006 at two centres. RESULTS The median follow-up was 36 months. The median age was 22 (range, 9-68). Two patients were postmenopausal. The most common symptoms at diagnosis included abdominal swelling or mass (72%) and abdominopelvic pain (62%). The location of the tumour was bilateral in 2 cases. Eight patients were in stage I, 4 patients in stage II, 17 patients in stage III, and 3 patients in stage IV. Eighteen patients underwent unilateral salpingo-oophorectomy, two bilateral salpingo-oophorectomy and two cystectomy, while 10 patients had total abdominal hysterectomy and two bilateral salpingo-oophorectomy. Of 32 patients who received postoperative chemotherapy, 27 were treated with a bleomycin/etoposide/cisplatin (BEP) regimen. Seventy-two percent of patients were alive at the last follow-up visit. Ten (31%) patients suffered from a recurrence of the disease with a median time to recurrence of 8 months (range, 6-28 months). The most common site of recurrence was the intra-abdominal space, with 8 patients. Only one patient who had recurrence could be salvaged. Fertility-sparing surgery was found at least as effective as radical surgery. While age, histology (mixed vs. pure), stage, tumour size, ascites, and marker levels were not found as prognostic factors, the presence of residual tumour (P=0.014) and BEP chemotherapy (P=0.016) were significant prognostic factors in univariate analysis. CONCLUSIONS In patients with ovarian YST, fertility-sparing surgery is as effective as radical surgery. Optimal cytoreductive surgery and standard BEP regimen are the most decisive prognostic factors. In these tumours, adjunctive therapeutic modalities to eradicate intra-abdominal disease and effective salvage therapy strategies are needed.

Immunohistochemical detection of p53 protein in rhabdomyosarcoma: association with clinicopathological features and outcome.

PURPOSE Alteration in the p53 tumor suppressor gene is the most common tumor specific genetic change identified in most major cancer types including rhabdomyosarcomas. To investigate the overexpression of p53 and its relation to clinical features and outcome in patients with rhabdomyosarcoma (RMS), an immunocytochemical study was performed. METHODS Formalin-fixed paraffin embedded tissue sections obtained from 42 cases of RMS were immunostained with a mouse monoclonal antibody p53-D07. Staining was assessed by evaluating the percentage of p53 immunopositive cancer cell nuclei. RESULTS Nuclear accumulation of p53 protein was detected in 8 of 42 (19%) samples. Clinical analyses of patients demonstrated no correlation between positive staining and age, sex, histological subtype, stage and overall survival. This analysis, however, was limited by the small number of patients who demonstrated p53 immunostaining. Nonetheless, a statistically significant association was observed between p53 expression and adverse outcome. Nuclear p53 expression was associated with disease progression or recurrence (p <0.001) and with a worse event free survival (p = 0.0015). CONCLUSION The nuclear p53 immunoreaction rate is low in RMS, but p53 expression appears to correlate with poor prognosis.

Hypertrophic osteoarthropathy and intrathoracic Hodgkin disease of childhood.

BACKGROUND Hypertrophic osteoarthropathy (HOA), well known in adults, is rarely encountered in children. The clinical features include clubbing of the fingers and toes, arthritis, and painful periosteal new bone formation of the tubular bones. The association of malignant disorders with HOA is more common in adults than in children. CASE In this paper, a 12-year-old boy with intrathoracic Hodgkin disease and HOA is presented and four other children with HOA and Hodgkin disease in the literature reviewed. DISCUSSION The presence of HOA has been thought to be a bad prognostic sign, but complete remission of Hodgkin disease and regression of clinical signs and symptoms of HOA were attained in our patient after chemotherapy and radiotherapy, and continue during 9 months post-therapy follow-up. CONCLUSIONS HOA accompanying a malignant tumor in children is very rare. Only 5 cases have been associated with Hodgkin disease, including the present boy. It is important that patients with symptoms of HOA and an intrathoracic mass be examined carefully to rule out a malignancy.

TREATMENT OF WILMS TUMOR: A Report from the Turkish Pediatric Oncology Group (TPOG)

Aim: To standardize diagnosis and treatment of childhood Wilms tumor (WT) in Turkey. Methods and patients: Between 1998 and 2006, WT patients were registered from 19 centers. Patients <16 years with unilateral WT whose treatment started in first postoperative 3 weeks were included. Treatments were stage I favorable (FH) and unfavorable histology (UH) patients, VCR + Act-D; stage IIA FH, VCR + Act-D; stage IIB FH, VCR + Act-D + radiotherapy (RT); stage III–IV FH, VCR + Act-D + adriamycin (ADR) + RT; stages II–IV UH tumors, VCR + Act-D + ADR + etoposide + RT. Results: 165/254 registered cases were eligible (bilateral, 5.9%) [median age 3.0 years; M/F: 0.99; 50/165 cases ≤2 years]. 9.7% cases had UH tumors. Disease stages were stage I 23.6%; IIA 36.4%; IIB 5.5%; III 22.4%; IV 12.1%. Cases >2 years had significantly more advanced disease. 1/11 cases with recurrent disease died; 2/165 had progressive disease, 2/165 had secondary cancers, and all 4 died. In all cases 4-year OS and EFS were 92.8 and 86.5%, respectively. Both OS and EFS were significantly worse in stage IV. Conclusions: Despite problems in patient management and follow-up, treatment results were encouraging in this first national experience with a multicentric study in pediatric oncology. Revisions and modifications are planned to further improve results and minimize short- and long-term side effects.

Malignant Ovarian Germ Cell Tumors A Single-Institution Experience

Objective:To evaluate the clinicopathologic prognostic factors in malignant ovarian germ cell tumors. Methods:We reviewed the medical records of 70 patients treated from 1990 to 2006 at our center. Clinical data including demographics, stage, surgery, chemotherapy, survival, menses status, and fertility were collected from patients’ charts. Results:Median age was 22 years (range, 9–68). The histologic subtypes included 36 dysgerminomas, 11 yolk sac tumors, 3 immature teratomas, 1 embryonal carcinomas, and 19 mixed types. The most striking clinicopathologic finding was a history of concomitant immunosuppressant therapy, which was observed in 2 patients. Two patients had contralateral sex-cord tumors at presentation and follow-up. During a median follow-up period of 4.6 years, 11 patients had recurrence. The median time to recurrence was 8 months (6–28 months). Recurrences appeared in the abdominopelvic cavity in 9 out of 11 patients. Only one could be salvaged with second-line chemotherapy. Cumulative survival rate was 97% and 60% in patients with dysgerminoma and nondysgerminoma, respectively. Nondysgerminoma histology and residual tumor after surgery were unfavorable prognostic factors (P < 0.001 and P = 0.015). Fertility-sparing surgery was as effective as radical surgery among all eligible patients. Of patients with known menstrual status, 96% had regular menses. Of the 8 patients who opted for conception among these patients, 7 delivered healthy infants. Conclusions:Nondysgerminomas have an aggressive clinical course. New treatment strategies are needed for eradication of abdominopelvic disease at initial diagnosis and recurrent setting. Occurrence of malignant ovarian germ cell tumors may be associated with immunosuppression in some patients. Sex-cord stromal tumors may present with bilateral involvement. It is possible to maintain fertility after fertility-sparing surgery followed by chemotherapy.

Rhabdomyosarcoma of the biliary tree

A 14-year-old girl was admitted to a local university hospital with complaints of right upper abdominal pain that had lasted for 1 year and abdominal distention for 1 week. On physical examination the abdomen was found to be distended and the liver was 2 cm below the right costal margin. Complete blood count, biochemistry and serum alpha-fetoprotein levels were found to be within normal limits. A sonogram and computed tomography (CT) of the abdomen revealed an enlarged liver with a mass of heterogeneous structure with cystic areas and septations. The chest X-ray and CT of the thorax and whole body bone scan were normal. The patient underwent laparotomy. Upon surgical examination, a 20 × 25 × 30 cm mass in the liver filled with hemorrhagic and necrotic material was observed. Partial right lobectomy and cholecystectomy were performed. No other intraabdominal mass was seen. Histopathologic examination revealed an infiltration consisting of loose myxoid and hypercellular areas. The cells were round or spindle shaped with scant cytoplasms. There were also cells with prominent eosinophilic cytoplasms characteristic of rhabdomyoblasts. Focal areas of pleomorphic cells were observed. Tumor necrosis was prominent. In some parts of the tumor, the surface was covered by a layer of cuboidal cells (bile duct epithelium) and beneath this epithelium there was a dense cellular zone, the so-called ‘cambium layer’. Immunohistochemical studies revealed a positive reaction for desmin and vimentin in tumoral cells. Pathologically, the tumor was consistent with a botryoid RMS of the intrahepatic bile ducts (Fig. 1). A sampled lymph node was reactive and the gallbladder was normal. Surgical margins were microscopically negative. The patient was referred to the Oncology Institute, Istanbul University, for further treatment and follow up. She was diagnosed as a group I rhabdomyosarcoma. Chemotherapy consisting of vincristine (1.5 mg/m 2 on day 1), actinomycin-D (45 μ g/kg on day 1), and cyclophosphamide (2 g/m 2 on day 1) (VAC) with mesna protection was initiated. Vincristine had to be abandoned due to severe neurotoxicity (drop-foot) at week 6. Actinomycin-D and cyclophosphamide was administered every 3 weeks for the first 12 weeks and at weeks 16, 20, 23, 29, 32, 38, 41, 47, and 50. The courses of chemotherapy were uneventful except grade 2–3 anemia, grade 2–3 neutropenia, trombocytopenia and drop-foot. On radiotherapy consultation, it was decided not to administer radiotherapy because a complete removal of the tumor with negative margins could be achieved. Chemotherapy was terminated at the end of 1 year. The patient is alive with no evidence of disease 40 months after termination of chemotherapy.

Prognostic value of proliferating cell nuclear antigen immunostaining in pediatric rhabdomyosarcomas

Background : The levels of proliferating cell nuclear antigen (PCNA) are almost negligible in long‐term quiescent cells and increase dramatically during the cell cycle. Recently, the monoclonal antibodies to PCNA have been used to demonstrate the proliferative component of paraffin‐embedded tumor tissues. It has been shown to be available as a simple histological marker of proliferative activity and the PCNA labeling index has been correlated with the prognosis of several malignant neoplasms.