Use of intracavitary cisplatin for the treatment of childhood solid tumors in the chest or abdominal cavity.

PURPOSE: Intracavitary (IC) delivery of cisplatin (CDDP) has been used in the treatment of a variety of adult malignancies based on the favorable pharmacokinetics obtained locally. Since IC CDDP has not been reported in children, we studied its use in a group of pediatric patients with regard to safety, toxicity, pharmacokinetics, and responses. PATIENTS AND METHODS: Eleven patients with an age range of 8 months to 21 years with diagnoses of rhabdomyosarcoma (n = 5), pleuropulmonary blastoma (n = 2), osteosarcoma (n = 2), Ewing's sarcoma (n = 1), and malignant rhabdoid tumor of the kidney (n = 1) were studied. Eight patients received intrapleural (IPL) CDDP and three received intraperitoneal (IP) CDDP, either at diagnosis (n = 3) or relapse (n = 8), for malignant pleural effusion (n = 3), malignant ascites (n = 2), pleural-based tumor (n = 4), pulmonary metastases (n = 1), or abdominal tumor spillage (n = 1). RESULTS: IC CDDP was well tolerated by pediatric patients. Two patients experienced a transient increase in serum creatinine levels (> two times baseline) and two patients experienced severe neutropenia (absolute neutrophil count < 500/microL). Pharmacokinectic measurements showed a 40-fold advantage for the pleural cavity versus serum after IPL CDDP and serum levels comparable to those achieved with systemic administration of CDDP. Four of five patients who received IC CDDP for malignant ascites or pleural effusion had at least a temporary response. Only three of 11 patients studied had local recurrences following IC CDDP. There are currently four survivors in the study group, including two long-term survivors at greater than 8 years since IPL CDDP treatment. CONCLUSION: The safety, toxicity, and pharmacokinetics of IC CDDP in pediatric patients are similar to that reported in adult patients. The low incidence of local recurrence following IC CDDP in this group of largely relapsed patients suggests that further study of IC CDDP for pediatric patients is warranted.

Results of a pilot study of hyperfractionated radiation therapy for children with brain stem gliomas.

The majority of children with brain stem gliomas develop progressive disease within 18 months of diagnosis and treatment. Radiotherapy (RT) is of transient benefit in most patients and higher total doses of RT have been related to improved survival. The amount of RT which can be given is limited by the tolerance of the surrounding brain. Hyperfractionated RT theoretically allows higher doses of RT to be tolerated by the brain. Sixteen children with brain stem gliomas were treated on a hyperfractionated RT schedule, receiving 120 cGy of RT twice daily, to a total dose of 6480 cGy. All patients tolerated treatment well. Eleven of 15 (73%) evaluable patients had a response to treatment and two (13%) others had stable disease. One patient developed progressive disease during treatment. All patients were tapered off steroids by the completion of treatment. Thirteen of 16 (81%) patients developed progressive disease at a median of 7 months after diagnosis and three remain in remission 8, 12, and 15 months following diagnosis. These results were similar to those of historical controls. Two patients were surgically explored at time of relapse and 5 have had an autopsy. No acute or subacute neurologic toxicity was seen; but long-term detrimental effects on brain could not be assessed. The implications of this study are that escalations of the dose of hyperfractionated RT can be entertained for children with brain stem gliomas.

Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases.

Inflammatory myofibroblastic tumor (IMT) or inflammatory pseudotumor is a spindle cell proliferation of disputed nosology, with a distinctive fibroinflammatory and even pseudosarcomatous appearance. Although the lung is the best known and most common site, inflammatory myofibroblastic tumor occurs in diverse extrapulmonary locations. We report our experience with 84 cases occurring in the soft tissues and viscera of 48 female patients and 36 male patients between the ages of 3 months and 46 years (mean, 9.7 years; median, 9 years). A mass, fever, weight loss, pain, and site-specific symptoms were the presenting complaints. Laboratory abnormalities included anemia, thrombocytosis, polyclonal hypergammaglobulinemia, and elevated erythrocyte sedimentation rate. Sites of involvement included abdomen, retroperitoneum, or pelvis (61 cases); head and neck, including upper respiratory tract (12 cases); trunk (8 cases); and extremities (3 cases). The lesions ranged in size from 1 to 17 cm (mean, 6.4; median, 6.0). Excision was performed in 69 cases. Eight had biopsy only. Five patients received chemotherapy or radiation in addition to undergoing biopsy or resection as initial treatment. Sixteen patients had multinodular masses involving one region. Clinical follow-up in 53 cases revealed that 44 patients were alive with no evidence of disease, four were alive with IMT, and five were dead. Thirteen patients had one or more recurrences at intervals of 1-24 months (mean, 6 months; median, 10 months). No distant metastases were documented. The five patients who died had complications either due to the location of the lesion (heart, peritoneum, retroperitoneum, or mesentery) or related to treatment (lymphoproliferative disorder following hepatic transplantation; sepsis following wound infection). The abdominal masses were the largest. All tumors were firm and white with infiltrative borders and focal myxoid change. Three basic histologic patterns were recognized: (a) myxoid, vascular, and inflammatory areas resembling nodular fasciitis; (b) compact spindle cells with intermingled inflammatory cells (lymphocytes, plasma cells, and eosinophils) resembling fibrous histiocytoma; and (c) dense plate-like collagen resembling a desmoid or scar. Immunohistochemistry demonstrated positivity for vimentin, muscle-specific actin, smooth muscle actin, and cytokeratin consistent with myofibroblasts. Based on this series, inflammatory myofibroblastic tumor is a benign, nonmetastasizing proliferation of myofibroblasts with a potential for recurrence and persistent local growth, similar in some respects to the fibromatoses.

Dural venous sinus thrombosis in acute lymphoblastic leukemia.

Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One patient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic cells. Attention is drawn to this potentially treatable cause of central nervous system symptoms in childhood leukemia. Angiography is the diagnostic test of choice and can also demonstrate intracerebral hematoma and subdural hematoma, if present. Sinus thrombosis can occur either during exacerbation or remission of the basic leukemic process. The possibility that chemotherapeutic techniques predispose toward this complication is raised.

Mutant fetal hemoglobin causing cyanosis in a newborn.

A well but cyanotic newborn was found to have a mutant gamma-globin chain, leading to a functionally abnormal fetal hemoglobin. A single amino acid substitution was found in a site consistent with known adult M hemoglobins. This patient showed no clinical evidence of cyanosis at 5 weeks of age as gamma-chain synthesis was replaced by beta-chain synthesis. A sibling born 20 months later was also cyanotic and the same mutant hemoglobin was found.

An afterloading brachytherapy device utilizing thermoplastic material.

An afterloading brachytherapy device for treatment of residual cancer in an enucleated orbit with two cesium-137 sources was designed using a thermoplastic material, Aquaplast. The device consists of a face-mask support held in place with elastic bands around the head and an acrylic afterloading applicator. The device is very easy to make, holds the sources firmly in place, allows full mobility of the patient, and gives excellent dose distribution to the target area. It was easily tolerated by a 7-year-old child during the 50 h of treatment.

Acute megakaryocytic leukemia (M7) in children.

We analyzed the clinical and laboratory features of eight children (median age, 20 months; range, 13 months to 11 years) with acute megakaryocytic leukemia (M7) and compared the findings with those reported in the literature. The diagnosis was supported by ultrastructural examination for platelet peroxidase or immunophenotyping for glycoprotein IIb/IIIa or the von Willebrand factor protein. Two patients had Down's syndrome. Initial findings included anemia (in all patients), thrombocytopenia (in six), myelofibrosis (in three), lytic bone lesions (in two), and pronounced leukocytosis (in one). Stem cell culture studies of peripheral blood specimens revealed an aberrant phenotype of the megakaryocytes in one patient and reversal to a normal pattern after successful therapy. Remission was achieved in seven of the eight patients after aggressive chemotherapy, and four patients remained in remission 27 to 57 months after diagnosis. Three of these four patients underwent allogeneic bone marrow transplantation. M7 leukemia is not infrequent in children younger than 3 years of age, especially in those with Down's syndrome. The availability of monoclonal antibodies specific to restricted antigens of the megakaryocytic lineage has made the diagnosis of M7 leukemia both possible and practical.

Neuroblastoma presenting as central nervous system disease.

Neuroblastoma may be extremely difficult to recognize, particularly when the tumor presents as a primary central nervous system disease. Central nervous system involvement may be considered as primary intracerebral neuroblastoma, metastases to the cranium from an occult primary, primary intraorbital neuroblastoma originating in the ciliary ganglion, metastatic intraorbital neuroblastoma from an occult primary, primary intraspinal neuroblastoma originating in dorsal root ganglia, intraspinal metastatic disease, and distant effects such as myoclonic encephalopathy. Primary neuroblastoma within the ciliary ganglion and primary intraspinal neuroblastoma are extremely rare entities. Illustrative cases the demonstrate the broad spectrum of neurologic presentations are offered. The second known report of neuroblastoma in association with primary pulmonary hypoventilation (Ondine curse) is included.

Control of extraneural metastasis of a primary intracranial nongerminomatous germ-cell tumor. Case report.

Primary intracranial germ-cell tumors are infrequently occurring neoplasms which most often arise in the pineal or sellar regions. Germinomas are seen more frequently than nongerminomatous germ-cell tumors; they are often curable with radiotherapeutic approaches, or with chemotherapy in the rare instance of extraneural metastasis. Nongerminomatous germ-cell tumors are relatively radioresistant and when extraneural metastasis has occurred, they have been fatal in all of the 32 previously reported cases. The case of a 14-year-old girl with a mixed malignant germ-cell tumor arising in the pineal region is reported. Extraneural metastasis to the lung developed 12 months after whole-brain radiotherapy was completed. She was treated with etoposide (VP-16), high-dose cisplatin, vinblastine, and bleomycin and is currently without evidence of disease 46 months postmetastasis.

Primary mediastinal hemangiopericytoma with fatal outcome in a child.

Hemangiopericytoma occurs infrequently in children, and mediastinal sites are exceedingly rare. We report a case of mediastinal hemangiopericytoma in a 4-year-old child, which resulted in the patient's death due to large size, anatomic location, and associated perioperative bleeding. The pathologic diagnosis was established on the basis of light microscopic, immunohistochemical, and electron microscopic features. The presentation and clinical course of this case contrast with those of congenital or infantile hemangiopericytoma, which generally has a favorable outcome. Hemangiopericytoma should be considered in the differential diagnosis of large mediastinal masses in children.

Paratesticular malignant mesothelioma associated with abdominoscrotal hydrocele.

This is the report of 14-year-old boy with a malignant mesothelioma of the tunica vaginalis contained in an abdominoscrotal hydrocele. A review of the literature shows that this aggressive tumor is very rare and has been reported only in adults.

Jaundice as a paraneoplastic phenomenon in a T-cell lymphoma.

An adolescent male developed severe unexplained cholestatic jaundice 3 mo before diagnosis of mediastinal non-Hodgkin's lymphoma (T-cell, late thymic phenotype). There was no anatomic obstruction to bile flow, no evidence for an infectious etiology, and no neoplastic involvement of the liver or bile ducts. A paraneoplastic phenomenon is postulated because the jaundice resolved after treatment of the lymphoma. We suggest that occult lymphoma must be added to the differential diagnosis of unexplained intrahepatic cholestasis.

Mixed conventional and desmoplastic infantile ganglioglioma: an autopsied case with 6-year follow-up.

We describe a case of desmoplastic infantile ganglioglioma (DIG) arising in the ventral diencephalon of a 3-1/2-month-old boy. On biopsy, the tumor featured a desmoplastic, S-100 protein and GFAP immunoreactive stromal element, as well as a variable spectrum of ganglion cells. Electron microscopy demonstrated astrocytes, and morphologically fibroblasts, as well as neurons containing 120-nm dense core granules. In addition, tubular structures composed of tightly apposed cells with features of astrocytes and of Schwann-like cells were also noted. Devoid of fibroblasts, the tubular structures were surrounded by a single basal lamina. At autopsy 6 years later, the multinodular, cystic mass had replaced the diencephalon, extended into both temporal lobes as well as the optic nerves, and showed marked leptomeningeal involvement. Microscopically, superficial portions of the tumor consisted of typical DIG, whereas deep, nondesmoplastic portions exhibited pattern variation ranging from pilocytic astrocytoma to ganglioglioma and gangliocytoma. There was also a minor element of small, 'primitive-appearing' neuroepithelial cells. Dysplastic ganglion cells variously reactive for neurofilament protein and synaptophysin were present throughout the tumor. Our study not only confirms DIG as a variant of ganglioglioma, one capable of slow growth, infiltration, and fatal progression but suggests that its differentiating potential includes elements of both the central and peripheral nervous systems. If so, their derivation may be from multipotential cells of the neural plate.

The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia.

Hemostatic function was studied sequentially in 12 children receiving L-asparaginase, vincristine, and prednisone as remission induction chemotherapy for acute lymphoblastic leukemia. The three-week period of L-asparaginase therapy was characterized by progressive decreases in plasma antithrombin, plasminogen, and fibrinogen concentrations, and by progressive increases in plasma clotting times (prothrombin time, partial thromboplastin time, thrombin time). Platelet counts rose rapidly during the third and fourth weeks of therapy as bone marrow remission was achieved. Factor V levels increased steadily during a five-week period, perhaps related to vincristine or prednisone therapy. Recent reports of thrombosis and hemorrhage in children and adults receiving L-asparaginase may be explained by this complex set of abnormalities in coagulation and coagulation control.

Intrathoracic extravasation of sclerosing agents associated with central venous catheters.

Two children receiving continuous infusions of vesicant chemotherapy through central venous catheters (CVCs) developed venous thrombosis, and intrathoracic extravasations ensued. One child receiving a continuous vincristine infusion presented with signs of thoracic venous obstruction, fever, and respiratory distress and had pleural effusions and pulmonary infiltrates on his chest roentgenogram. The other child was receiving a continuous doxorubicin infusion and developed superior vena cava thrombosis and retrograde extravasation along the catheter tunnel site. Both children improved after chemotherapy was discontinued and the CVCs removed. Catheter placement and the continuous infusion of sclerosing agents are discussed.

Autoimmune neutropenia of infancy and early childhood.

Forty-one children were identified with autoimmune neutropenia of infancy and early childhood (absolute neutrophil count [ANC] less than 500/microliters and demonstrable serum antineutrophil antibodies). There were 21 boys and 20 girls; the median age at diagnosis was 11 months (range 5-38 months). No life-threatening infections occurred. There was a gradual upward trend in ANC in all patients over many months, with 87% having an ANC > 1000/microliters by 24 months from diagnosis. Among various clinical and laboratory parameters analyzed statistically, only younger age at diagnosis was associated with earlier neutrophil recovery. There was no association between degree or duration of neutropenia and sex, race, antibody reactivity, or presence of serious illness at diagnosis.

Transient autoimmune neutropenia due to anti-NA1 antibody.

A 6-month-old girl developed severe, but transient neutropenia due to an antibody against a neutrophil-specific antigen, NA1. The mean absolute neutrophil count was 380/microliter for 2 months and spontaneously returned to normal as the anti-NA1 antibody disappeared. After recovery, the NA1 antigen was demonstrated on the patient's neutrophils. No etiology was found. There was no therapy directed at suppressing the antibody or increasing the neutrophil count. Life-threatening infection did not occur during the neutropenia.