Malignant Lymphomas Other than Hodgkin’s Disease

This report describes a unique clinicopathologic entity characterized as a malignant small cell tumor of the thoracopulmonary region in 20 children and adolescents (average age 14.5 years). There was a female predilection (75%) for this tumor which appeared to originate in the soft tissues of the chest wall or the peripheral lung. The neoplasm tended to recur locally and did not seem to disseminate as widely as some of the other small cell tumors of childhood (rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma and malignant lymphoma). However, the median survival was only 8 months. Electron microscopy of 3 cases suggested a neuroepithelial derivation, but, at the present, the histogeneis remains a subject for further investigation.

Malignant small cell tumor of the thoracopulmonary region in childhood. A distinctive clinicopathologic entity of uncertain histogenesis

Summary Progress in the treatment of Ewing's sarcoma, the second most common bone tumour in children and adolescents, has improved survival from about 10% in the period before chemotherapy was introduced to about 75% today for patients with localised tumours. However, patients with metastases still fare badly, and the therapy carries short-term and long-term toxicities. Multidisciplinary care is indispensable for these patients. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. Cooperative group studies have led to chemotherapy regimens using the same drugs (vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide), although the exact regimens differ in Europe and North America. The EWS–ETS family of gene fusions and their downstream effects in Ewing's sarcomas provide opportunities for new approaches to treatment. These include the inhibition of the fusion gene or its protein product, and pathways related to IGF1 and mTOR. Inhibition of tyrosine kinases, exploitation of non-apoptotic cell death, and interference with angiogenesis are promising new approaches. With many new approaches and relatively few patients, it will be challenging to integrate new and established treatments through clinical trials.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70286-4.pdf

Ewing's sarcoma

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study.

This article reviews the pathologic features and the behavior of 39 small, round, or oval cell sarcomas occurring in the soft tissues and considered histologically indistinguishable from Ewing's sarcoma of bone. The tumors affected chiefly young adults (median age 20 years) and most commonly involved the soft tissues of the lower extremity and the paravertebral region. Microscopically, they consisted of solidly packed small, round, or ovoid cells of great uniformity, arranged in sheets or lobules separated by strands of fibrous connective tissue. The nucleus of the tumor cells contained finely divided chromatin, a distinct nuclear membrane, and frequently a minute nucleolus. The scanty ill-defined cytoplasm contained varying amounts of glycogen. Sometimes the histologic picture was dominated by a "peritheliomatous" pattern, or by large areas of necrosis or hemorrhage. Followup data ranging from 1 month to 14 years were available in 35 of the 39 cases (93%). Of these, 13 were alive and 22 had died. In the majority of the fatal cases, the clinical course was rapid; metastatic lesions developed within a few months after the primary tumor was excised. The lungs and the skeleton were the two most common sites of metastasis. Cure may be achieved by wide local excision of the tumor at an early stage of the disease, combined with radiation therapy and chemotherapy.

Extraskeletal neoplasm resembling Ewing's sarcoma

Eighty-six children with non-Hodgkin's lymphoma were studied from 1964 to January 31, 1975. Seventy-six percent of the 43 patients in the nonprotocol group had far advanced disease, and 76% had Rappaport's diffuse histology. Only 11% of these patients survived free of disease. The second group of 43 patients received the LSA2L2 protocol. Seventy-six percent had advanced disease and 86% diffuse histology. Of these patients 76% are surviving free of disease with a median observation time of 25+ months. Fifty-one percent of the survivors are off therapy and without evidence of disease. Prognostic factors such as primary sites, stages, histology, and others are discussed. The most important prognostic factor is early and aggressive therapy, and the achievement of a complete response status within 1-2 months from onset of therapy.

Non-Hodgkin's lymphoma in children. A comparative study of two modalities of therapy.

Adjuvant chemotherapy was added to local radiation therapy for patients with Ewing's sarcoma to treat widespread microfoci of disease presumed to be present at the time of diagnosis. Since June 1970, 12 children have been treated with radiation therapy and sequential adjuvant chemotherapy: dactinomycin, adriamycin, vincristine, and cyclophosphamide, continued for 2 years. Two children developed reversible congestive heart failure after cumulative adriamycin doses of 905 mg/m2 in one patient and 720 mg/m2 in another patient who had mediastinal irradiation. Adriamycin is now generally limited to cumulative doses of 720 mg/m2 but is further limited to 500 mg/m2 in children who receive mediastinal or pulmonary irradiation. Of 12 children entered into this study and followed for from 10 to 37 months, all continue in disease-free remission without evidence of recurrent tumor, metastatic tumor, or central nervous system disease.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197402%2933%3A2%3C384%3A%3AAID-CNCR2820330213%3E3.0.CO%3B2-T

Disease-free survival in children with Ewing's sarcoma treated with radiation therapy and adjuvant four-drug sequential chemotherapy

In a study of non-Hodgkin's lymphoma in children, 104 children were treated and followed at Memorial Sloan-Kettering Cancer Center from 1964 throughout June 1974. Forty-three patients, previously treated and untreated, received a nonspecific group of various chemotherapeutic agents and attained an 11% disease-free survival rate. A second group of 18 previously untreated patients, who received a chemotherapeutic regimen consisting of cyclophosphamide alone, achieved a 33% disease-free survival rate. The last group, 43 previously untreated patients (77% of whom had far advanced disease and 86% of whom had diffuse histological types) who received a new and intensive multiple-drug regimen (the LSA2-L2 protocol) consisting of induction, consolidation, and maintenance phases, has maintained an 81% disease-free survival rate after a median observation time of 21+ months. Although nervous system involvement and recurrence or metastases at any time are poor prognostic factors, initial marrow involvement and the amount of bulky disease are no longer considered negative prognosticators when intensive treatment is initiated immediately after diagnosis, is continued for 2--3 years, and includes radiation therapy to sites of bulky disease and CNS prophylaxis. The LS2-L2 treatment is effective in accomplishing the dual aims of not only increasing the numbers of disease-free patients but also prolonging their survival.

Non-Hodgkin's lymphoma in children.

Twenty-nine children under 15 years of age with embryonal rhabdomyosarcoma were treated according to a multidisciplinary protocol (T-2). The protocol consisted of surgical removal of the tumor if possible, followed by chemotherapy, and also with radiation therapy in patients with gross or microscopic residual disease. Radiation therapy was given in the 4500-7000 rads range. The chemotherapy consisted of cycles of sequential administration of dactinomycin, Adriamycin, vincristine, and cyclophosphamide, with obligatory periods of rest. The drug therapy was continued for 2 years. Following surgery, clinicopathologic staging of the disease revealed 10 patients with no residual disease (I-A), 5 with microscopic residual disease (I-B), 5 with unresectable tumors (II), 6 with unresectable tumors plus regional lymph node involvement (III), and 3 with disseminated tumors (IV). Twenty-four (82%) of the patients (20 Stages I-II, 4 Stage III) are alive with no evidence of disease for 4 plus to 42 plus months. These results are superior to those achieved between 1960-1970 among 108 children treated at Memorial Sloan-Kettering Cancer Center.

Multidisciplinary treatment of embryonal rhabdomyosarcoma in children.

Twenty-three patients with rhabdomyosarcoma and 15 patients with Ewing's sarcoma, treated with radiation therapy to the local site and systemic multiagent chemotherapy are described. Acute reactions from combination chemotherapy and radiation therapy were noted in both groups of patients. These reactions often appeared after low doses of irradiation, required unplanned interruptions of treatments, and in some patients, led to discontinuation of radiation therapy. The chronic effects on normal tissues in both groups of patients have been severe in several cases.

Giulio J. D'Angio

Papers

Non-Hodgkin's lymphoma in children. A comparative study of two modalities of therapy.

Disease-free survival in children with Ewing's sarcoma treated with radiation therapy and adjuvant four-drug sequential chemotherapy

Non-Hodgkin's lymphoma in children.

Multidisciplinary treatment of embryonal rhabdomyosarcoma in children.

Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma.