Colorectal carcinoma in childhood and adolescence: a clinicopathologic review.

PURPOSE: Pediatric colorectal carcinoma (CRC) is rare, but the available data suggest that it is more likely than adult CRC to be advanced at presentation and to have a poor outcome. We sought to better characterize pediatric CRC. PATIENTS AND METHODS: We reviewed the clinical and pathologic features, prognostic factors, and outcome of CRC in 77 children and adolescents (ages 7 to 19 years) referred to St Jude Children's Research Hospital between 1964 and 2003. RESULTS: At presentation, 76 patients had one or more signs or symptoms of CRC (abdominal pain, altered bowel habits, weight loss, anemia). Tumors were evenly distributed between the right and left colon; 62% were mucinous adenocarcinoma. At presentation, 86% of patients had advanced-stage disease; more than half had distant metastases. Overall outcome was poor. Advanced stage and mucinous histology were significant predictors of adverse outcome. Stage-specific survival at 10 years was 67% +/- 27% (stage 1), 38% +/- 15% (stage 2), 28% +/- 11% (stage III), and 7% +/- 4% (stage 4). Although no patient had a diagnosis of polyposis syndrome before diagnosis of CRC, 17 (22%) had colon polyps and eight (including two who previously underwent pelvic radiotherapy) had multiple polyps. CONCLUSION: Initial signs and symptoms of CRC are similar in pediatric and adult patients. The strikingly higher frequency of mucinous histology suggests that the biology of CRC differs in pediatric and adult patients and may contribute to poor outcomes. Children should be included in prospective clinical trials for CRC.

Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas: the St. Jude Children's Research Hospital experience.

BACKGROUND: Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period. METHODS: In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support. RESULTS: Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% +/- 11.2%. CONCLUSIONS: The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity.

Metastatic osteosarcoma.

BACKGROUND: The outcome of patients with metastatic osteosarcoma treated in two consecutive trials from 1986 to 1997 was analyzed to evaluate the efficacy of carboplatin-based multiagent chemotherapy and to identify prognostic factors. The initial study (OS-86) used ifosfamide, cisplatin, doxorubicin, and high-dose methotrexate, and the subsequent study (OS-91) used the same agents at similar doses, but carboplatin was substituted for cisplatin. METHODS: Twelve patients (median age, 15.1 yrs) were treated in OS-86 for osteosarcoma metastatic to the lung only (11 patients) or bone only (1 patient), and 17 patients (median age, 15.1 yrs) were treated in OS-91 for osteosarcoma metastatic to the lung only (12 patients), bone only (2 patients), lung and bone (2 patients), or other site (1 patient). RESULTS: Patients with metastatic disease enrolled in OS-86 and those with metastatic disease enrolled in OS-91 did not differ in terms of demographic features, histologic subtype, site of primary tumor, or site of metastases. There was a difference in survival according to treatment protocol (P = 0.054). All survivors (four of whom were enrolled in OS-86 and one of whom was enrolled in OS-91) had lung metastases only. Five-year survival estimates for patients with lung metastases only were 45.5 +/- 13.7% (OS-86) and 8.3 +/- 5.6% (OS-91) (P = 0.084). Unilateral lung metastases (P = 0.006), no more than three lung nodules (P = 0.014), and surgical remission (P = 0.001) were associated with improved survival probability. CONCLUSIONS: The poor outcome of patients with metastatic osteosarcoma treated in OS-91 justifies the use of cisplatin with its associated toxicity in patients with high-risk disease.

The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma.

BACKGROUND: It has been shown that induction high-dose interferon alpha-2b (IFN-alpha-2b) followed by maintenance therapy improves recurrence-free survival in adults with high-risk, resected melanoma. In this study, the feasibility and toxicity of this regimen were evaluated in newly diagnosed pediatric patients with Stage III melanoma involving regional lymph nodes. METHODS: Fifteen patients age

Brain metastases of malignant germ cell tumors in children and adolescents.

BACKGROUND: Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival. METHODS: The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period. RESULTS: Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors. CONCLUSIONS: Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.

Real-time polymerase chain reaction as an aid for the detection of SYT-SSX1 and SYT-SSX2 transcripts in fresh and archival pediatric synovial sarcoma specimens: report of 25 cases from St. Jude Children's Research Hospital.

Synovial sarcoma is the most common nonrhabdomyosarcomatous soft tissue sarcoma in children and adolescents and is characterized by a reciprocal t(X;18)(p11;q11) which results in the fusion of the SYT gene on chromosome 18q11 to either of two closely related genes, SSX1 (Xp11.23) or SSX2 (Xp11.21). Detection of this translocation or its resultant gene fusion by molecular methods is helpful in the pathologic diagnosis of synovial sarcoma, especially in poorly differentiated tumors. This study was designed to evaluate the utility of a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay to detect and distinguish SYT-SSX1 and SYT-SSX2 fusions in fresh and archival specimens of synovial sarcoma in pediatric patients seen at St. Jude Children's Research Hospital. In addition, the clinicopathologic features of the tumors with SYT-SSX1 vs. SYT-SSX2 fusions were compared. The 25 patients studied had a median age of 13 years 9 months (range 5 to 19 years). Estimates of survival and event-free survival at 5 years were 78.7 +/- 10.5% and 56.2 +/- 13.2%, respectively. Seventeen (68%) tumors were monophasic, eight (32%) were biphasic. Seven tumors contained poorly differentiated areas. Positive results for either SYT-SSX1 or SYT-SSX2 were obtained in 21/25 (84%) cases. Three cases did not have a detectable gene fusion and one had no amplifiable RNA. SYT-SSX1 transcripts were found in 18/24 (75%) of the tumors while SYT-SSX2 transcripts were identified in 3/24 (12.5%). All of the poorly differentiated tumors and seven out of eight tumors from patients who developed lung metastases had an SYT-SSX1 fusion transcript. Real-time PCR is useful in detecting and distinguishing SYT-SSX1 from SYT-SSX2 gene fusions in synovial sarcoma. Valuable aspects of this methodology are the applicability to both frozen and formalin-fixed samples, decreased labor costs, and the rapidity of results. In addition, distinguishing SYT-SSX1 from SYT-SSX2 fusions with these methods allow for prospective collection of information that may clarify issues of prognostic relevance.

Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma.

PURPOSE: To describe the clinical features, response to therapy, and outcome of pediatric patients with initially unresected nonmetastatic nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). PATIENTS AND METHODS: We retrospectively reviewed the presenting clinical features and tumor characteristics of all 40 pediatric patients with initially unresected nonmetastatic NRSTS who were seen at our institution between March 1962 and December 1996. A subset of 27 patients for whom complete treatment information was available was analyzed to determine whether response to therapy was associated with local disease control and event-free and overall survival. RESULTS: More than 70% of the 40 patients had tumors with high-risk features (tumor size > 5 cm, high grade, invasiveness). For the 27 patients included in the outcome analysis, 5-year event-free survival and survival estimates were 33% +/- 9% and 56% +/- 10%, respectively. Ten (37%) of these patients had a complete or partial response to neoadjuvant chemotherapy and/or radiotherapy, and only two of the 10 had residual tumor after surgery. Combined chemotherapy and radiotherapy seemed more effective than either modality alone in inducing a response, but the response to neoadjuvant therapy did not predict outcome. Most treatment failures were local, and postrelapse survival was poor (19% +/- 10%). CONCLUSION: Initially unresected NRSTS constitutes a unique subgroup of pediatric sarcomas that commonly present with high-risk features and respond poorly to neoadjuvant therapy. Only about one third of patients treated with multimodal therapy remain disease-free, and local control is the major limiting factor in achieving cure. More effective risk-directed treatments are needed for this unique subgroup of patients.