Warren W. Johnson

The central nervous system in childhood leukemia: I. The arachnoid

A histopathologic study was performed to evaluate the distribution and extension of intracranial leukemic infiltrates and their relationship to other morphological disturbances of the central nervous system (CNS) in childhood acute lymphocytic leukemia. Of 126 brains examined, 70 had arachnoid leukemia at the time of autopsy. The earliest evidence of leukemia was seen in the walls of superficial arachnoid veins. With more advanced arachnoid leukemia, the disease was seen to extend into the deep arachnoid surrounding blood vessels as they course through the brain. The arachnoid leukemia followed a predictable expanding pattern to eventual invasion of brain parenchyma with destruction of the pia‐glial membrane. Leukemic infiltrate at the capillary‐neural tissue interface was present only following destruction of pia‐glial membrane secondary to deep arachnoid leukemia. Arachnoid fibrosis and certain brain parenchymatous lesions were found in association with arachnoid leukemia. The brain lesions included gliosis, necrosis, cerebral hemorrhage, and nonhemorrhagic degenerative encephalopathy. This study demonstrates that CNS leukemia is primarily an arachnoid disease. Disturbances of brain parenchyma apparently result from leukemic extension through pia‐glial membrane or interference with local perfusion due to constriction of blood vessels by perivascular arachnoid leukemia.

Classification of chronic myelocytic leukemia in children

The present study was undertaken to define criteria for classification of chronic myelocytic leukemia in children and adolescents. From April, 1963 through July, 1971, 18 patients were available for study. Evaluation of the clinical, laboratory, and histopathologic features demonstrates three distinct subgroups: adult, juvenile, and familial chronic myelocytic leukemia. Parameters of most value in this distinction are the level of the white blood cell count, presence of thrombocytopenia or thrombocytosis, the bone marrow myeloid to erythroid ratio, and the presence or absence of well‐defined malpighian corpuscles in the spleen. One patient with acute lymphocytic leukemia in remission manifested some unique features and may represent a fourth form of chronic myelocytic leukemia, resulting from previous chemotherapy or irradiation. The use of chemotherapy has not significantly prolonged survival in our patients. Two patients with familial chronic myelocytic leukemia are surviving in remission 9 years following splenectomy.

Stage-related combined modality treatment of retinoblastoma. Results of a prospective study.

Forty‐two consecutive patients with retinoblastoma were evaluated by a new staging system and combined modality therapy instituted according to stage. Nineteen patients had bilateral tumors and 23 had unilateral tumors. The staging system was effective in identifying subpopulations of patients and successfully predicted those at greater risk of recurrence or death. Thirty‐nine of 42 patients survive (Median survival time, 42 months). Two of 4 children with tumor extension beyond the eye died while 37 of 38 children with tumor presumed confined to the eye survive. Toxicity of the chemotherapy was mild. Radiation therapy of intraocular tumor was associated with cataract formation but most children had satisfactory vision after extraction and the use of corrective lenses. Ophthalmologic findings did not always correlate with histologic extent of tumor and both should be used in planning and evaluating treatment. Recommendations are made on the role of chemotherapy and the need to reduce the morbidity of treatment.

Methotrexate-induced sudden fatal pulmonary reaction.

A teenage girl in bone marrow remission with acute lymphocytic leukemia died suddenly from pulmonary edema. She had taken her first oral doses of methotrexate and cyclophosphamide 10 hours previously when she was feeling well and was asymptomatic. One week previously she had received the last of four intrathecal injections of methotrexate. Autopsy showed marked pulmonary edema as well as chronic lung changes, as previously described in patients with methotrexate pneumonitis. There is usually at least a 12‐day interval from the onset of administration of methotrexate to the onset of the lung toxicity. The authors suggest the patient was sensitized by the intrathecal methotrexate and then reacted with angioneurotic edema of the lung when given the first oral dose of methotrexate. Careful examination for infectious agents, including electron microscopy, was negative.

Nemaline structures in polymyositis: A nonspecific pathological reaction of skeletal muscles

“NEMALINE MYOPATHY” was originally characterized as a congenital, nonprogressive disorder with unique, thread-like (nemaline) structures in the muscle fibers.1 “Late-onset rod myopathy” was subsequently described as an acquired muscle disease in which the rods were thought to represent a degenerative change.2 The concept that rod formation may be a nonspecific degenerative change rather than a specific disease was strengthened by studying other cases of “late-onset myopathy”3 and by finding rods in an increasing number of disorders.4 We have had a n unusual opportunity to study a patient having an initial muscle biopsy showing polymyositis and two subsequent biopsies showing nemaline structures. The patient, a 9-year-old girl, was first observed to have proximal muscle weakness a t age 10 months. The first (1964) muscle biopsy at age 4% years showed polymyositis b u t no nemaline rods. Two subsequent (1966 and 1967) muscle biopsies showed copious nemaline rods. We are reporting this case because it demonstrates the nonspecificity of rod formation, regardless of the number of rods or fibers involved, and challenges the concept of designating the “acquired’’ form of nemaline myopathy as a nosological entity.

Duration and severity of fatty metamorphosis of the liver following L‐asparaginase therapy

Histologic sections of liver obtained at postmortem examination from 31 patients who received L‐asparaginase therapy for various hematologic malignancies were reviewed to define the incidence, severity, and duration of fatty metamorphosis. Twenty‐seven of the patients had hepatic lipidosis of varying degrees of severity up to 261 days following the last dose of L‐asparaginase. The high frequency and the persistence of hepatic changes following L‐asparaginase could have an influence on subsequent therapy with other antileukemic agents that are metabolized by the liver or are themselves potentially hepatotoxic.

Comparison of daily versus weeklyl-asparaginase for the treatment of childhood acute leukemia

l -Asparaginase was administered intravenously by two dosage schedules to 19 children with acute leukemia refractory to conventional antileukemic agents. Nine patients with acute lymphocytic leukemia received the enzyme in a daily dosage of 4,000 I.U. per square meter of body surface area for 6 to 21 days. Ten patients, 7 with acute lymphocytic leukemia and 3 with acute myelocytic leukemia, received the enzyme in a dosage of 20,000 I.U. per square meter once weekly. Four patients with acute lymphocytic leukemia developed complete remission marrows. Two patients, one with acute lymphocytic leukemia and one with acute myelocytic leukemia, achieved partial remissions. Six patients died during the treatment period. All patients developed evidence of hepatic dysfunction. Toxicity appeared to be greater when l -asparaginase was administered daily rather than weekly. Prolongation of l -asparaginase therapy beyond 2 weeks is not indicated because of promptness of response by sensitive cells and potential toxicity of the agent.

Splenectomy and chemotherapy in acute myelocytic leukemia of childhood

This study was undertaken to explore the therapeutic and diagnostic value of splenectomy for children with acute myelocytic leukemia (AML) in remission. Of 29 consecutive untreated patients entering the study, 19 attained complete remission with mercaptopurine, vincristine, and 6‐azauridine. Chemotherapy during remission consisted of mercaptopurine daily and cytosine arabinoside weekly. Because remission lasted 2 months or less in 5 patients, they did not undergo splenectomy. Fourteen patients underwent splenectomy while clinically in complete remission. Splenectomy was tolerated well with no major complications. Gross abnormalities of the abdominal organs were found in 11 patients. Histologic leukemia was found in 12 patients, most often in the spleen. Negro children did not respond to therapy as well as Caucasian children. Central nervous system (CNS) leukemia terminated clinical remission in 7 of the 14 patients. Four patients remain in initial CNS and hematologic remission for 18 to 24 months, and four others remain in initial hematologic remission for 16 to 18 months. These results suggest that in children with AML, splenectomy may influence the activity of leukemia and prolong the duration of remission.

Ultrastructure of malignant histiocytoma arising in the acromion

The ultrastructural features of a malignant histiocytoma of the acromial process of the scapula were studied. Material was obtained from two surgical biopsy specimens and an amputation specimen from the tumor. Cells possessing characteristics of histiocytes, fibroblasts, xanthoma cells, and multinucleated giant cells were present throughout the tumor. Smaller numbers of undifferentiated cells and lymphocytes were also observed. Intimate cytoplasmic interdigitations between adjacent tumor cells were found, and instances of degenerating intracytoplasmic cells, possibly representing phagocytosis, were observed. Specimens stained with periodic acid-Schiff reagent with and without exposure to diastase, examined by light microscopy, showed that numerous cells contained phagocytized material consisting of degenerating cells rather than cytoplasmic glycogen. Intraumor lymphocytes apparently represented an inflammatory reaction to the tumor. The tumor giant cells and xanthoma cells were probably modified histiocytes. Results of the study were compared with previous reports of ultrastructural studies of malignant histiocytoma of soft tissues. Fundamental similarities between such studies and this one suggested that the progenitor cell is a histiocyte, whether arising in bone or in soft tissues, and that the progenitor cell is capable of differentiation in both histiocytic and fibroblastic directions.

Detection of subclinical and carrier states in Duchenne muscular dystrophy

Three methods of study, consisting of determinations of serum creatine phosphokinase and aldolase, electromyography, and muscle biopsy, were utilized to study clinically uninvolved members of nine families containing one or more known cases of muscular dystrophy. The combined use of these methods of study allowed detection not only of advanced myopathic changes, but also of minimal abnormalities considered characteristic of the heterozygous state. The graded findings formed a useful basis for a rational classification of abnormalities to denote “preclinical”, “carrier” and “presumptive carrier” states. In addition, results provided further indirect evidence that X-chromosome mosaicism may be operative in the inheritance of the Duchenne type of muscular dystrophy.