REVIEW ARTICLE

Acute Lymphoblastic Leukemia Occurring as a Second Malignant Neoplasm in Childhood: Report of Three Cases and Review of the Literature By Stephen P. Hunger, Jeffrey Skloar, and Michael P. Link Purpose: The long-term effects of childhood cancer and its therapy are a problem of increasing concern. One of the most important of these late effects is the development of second malignant neoplasms (SMNs), which occur in approximately 8% of children within 20 years of diagnosis of a malignancy. These secondary cancers may result (individually or in combination) from increased genetic susceptibility, the mutagenic effects of chemotherapy and/or radiation therapy, or chance. Whereas the development of acute nonlymphocytic leukemia (ANLL) as an SMN is a well-recognized phenomenon, acute lymphoblastic leukemia (ALL) has been infrequently described as an SMN in either adults or children. Patients and Methods: We report three patients treated at our institution in whom ALL developed as an SMN after treatment for neuroblastoma, Wilms' tumor, and Hodgkin's disease. These cases prompted us to review

FOR

the published literature for cases of secondary ALL in childhood. Patients whose initial malignancy was diagnosed at age less than 16 years were classified as pediatric patients. SMNs were defined as cancers of clearly distinct histologic type occurring 6 or more months after diagnosis of the first malignant neoplasm. Results: Including the three index cases, a total of 18 children with secondaryALL are reviewed, and the clinical features are discussed and compared with those of secondary ANLL. Conclusions: This review summarizes the published case histories of secondary ALL. The data suggest that ALL represents approximately 5% to 10% of the cases of acute leukemia that arise as SMNs in both adults and children. J Clin Oncol 10:156-163. o 1992 by American Society of Clinical Oncology.

MORE THAN 50 years, second malignant neoplasms (SMNs) have been described in patients with cancer. The initial case reports consisted predominantly of radiation-induced bone tumors and sarcomas.

malignancy in children, it has been infrequently reported as an SMN in both adults and children, and no 3

Later, after the introduction of multiagent chemother-

who developed T-cell ALL as an SMN. Two earlier children with secondary ALL after Wilms' tumor and

apy regimens, acute leukemias were noted with increasing frequency.1 2 The first comprehensive survey of SMNs in childhood was published by Tefft et al in 1968,3 and this was followed by a series of reports from the Late Effects Study Group (LESG) and others delineating the 3 extent of the problem. " In the past 2 decades, the published literature on SMNs has expanded rapidly. Acute nonlymphocytic leukemia (ANLL) has been well described as a secondary malignancy in both adults and children, especially after prior therapy with alkylating agents.'"' Although acute lymphoblastic leukemia (ALL) occurs much more frequently than ANLL as an initial

From the Departments of Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA. Submitted March 25, 1991; acceptedJuly 16, 1991. Supported by grant no. CA 34233 from the National Cancer Institute, NationalInstitutes of Health. J.S. is currently at the Department of Pathology, HarvardMedical School andBrigham and Women's Hospital,Boston, MA 02115. Address reprint requests to Stephen P. Hunger, MD, Division of Hematology/Oncology, Packard Children'sHospitalat Stanford, 725 Welch Rd, Palo Alto, CA 94304. © 1992 byAmerican Society of Clinical Oncology. 0732-183X/92/1001-0007$3.00/0

156

comprehensive series has been published. 6'11,14,15,1819,32-43 We recently encountered a patient with neuroblastoma

Hodgkin's disease have been seen at our institution; these three cases prompted us to review the published literature on this topic. PATIENTS AND METHODS Case Definition and Ascertainment We followed the definition of the LESG" in reviewing the literature: patients whose initial malignancy was diagnosed while they were less than 16 years of age were classified as pediatric patients. SMNs were defined as cancers of clearly distinct histologic type occurring at least 6 months after the diagnosis of the initial malignancy. To avoid confusion, cases of leukemia with lineage switch or infidelity and non-Hodgkin's lymphoma (NHL) with subsequent ALL were specifically excluded. In patients with more than two distinct cancers, all cases occurring after the first were classified as SMNs. In reviewing the literature, we included only those cases of leukemia that were clearly lymphoid; cases of undifferentiated leukemia or leukemia without further specification were excluded. Gene RearrangementStudies Immunoglobulin (Ig) and T-cell receptor (TCR) genes were assessed for rearrangements as previously described.4445 Briefly, DNA was extracted from mononuclear cells, digested to completion with appropriate restriction enzymes, and size-fractionated by

Journalof Clinical Oncology, Vol 10, No 1 (January), 1992: pp 156-163

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 8, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

SECONDARY ALL IN CHILDHOOD electrophoresis in agarose gel." Separated DNA fragments were transferred onto activated nylon membranes (Genatran-45;Plasco, Woburn, MA) and then hybridized with DNA probe fragments radioactively labeled by the random hexamer priming technique." The J,,, J42, and J, probes were used to assess rearrangements of the TCR P and y loci, respectively. 45 The J., C., and C, probes detect rearrangements of the Ig heavy and light chain genes."4

Case Histories Case 1. Patient no. 1 was diagnosed with stage D (Evans stage IV) neuroblastoma in April 1985. Sites of disease included a left adrenal mass, a large posterior mediastinal mass, multiple lytic bone lesions, and bone marrow involvement; urinary catecholamine levels were significantly elevated. The patient was treated for a total of 18 months with multiagent chemotherapy that included (cumulative doses in parentheses) cisplatin (720 mg/im2), teniposide (900 mg/mz), cyclophosphamide (16,050 mg/m2), doxorubicin (385 mg/m2), and etoposide (1,100 mg/m'). He also received 25 Gy of radiotherapy to the posterior mediastinum and right side of the neck. Therapy was completed in October 1986, at which time the patient demonstrated no evidence of residual disease. For the next 2 years he remained free of disease; serial bone marrow examinations, scans of sites of previous disease, and urinary catecholamine levels were normal during this time period. In October 1988 (44 months after diagnosis of neuroblastoma and 24 months after the completion of therapy), the patient returned to the clinic with a short history of bone pain, fever, and malaise. Upon physical examination, hepatosplenomegaly and diffuse bony tenderness were noted. Peripheral blood cell counts revealed thrombocytopenia and a leukocyte count of 109 x 109 /L (83% lymphoblasts). A chest x-ray showed no evidence of a mediastinal mass. Bone marrow examination disclosed replacement of normal marrow elements with lymphoblasts of L1 morphology that were Sudan black and nonspecific esterase-negative. Periodic acid-Schiff reaction was strongly positive with a coarse blocking pattern, and acid phosphatase was positive. Immunophenotyping studies revealed that the blasts expressed the CD2, CD4, CD5, CD7, and CD8 antigens, but not HLA-DR. Cytogenetic studies of bone marrow revealed a 46, XY karyotype without clonal abnormalities. Posterior iliac crest bone marrow biopsies confirmed the diagnosis of acute leukemia; however, there were also extensive areas of recurrent neuroblastoma. Thus, diagnoses of recurrent neuroblastoma and concurrent T-cell ALL were made. After 6 weeks of chemotherapy (prednisone, vincristine, asparaginase, cyclophosphamide and cytarabine) a complete remission of the T-ALL was obtained, but there was progression of the neuroblastoma as evidenced by more extensive marrow involvement, increasing urinary catecholamine levels, and progressive lytic skull lesions. Despite further therapy, the patient died of progressive neuroblastoma. An autopsy was not performed. Case 2. Patient no. 2 was noted to have an asymptomatic left flank mass on routine physical examination at the age of 5 years in 1968. She underwent resection of a 10- x 7-cm well-encapsulated Wilms' tumor that was clinically defined as group I. Postoperatively, she received dactinomycin (15 ý±g/kg/d for 5 days) followed by 40 Gy of radiotherapy to the tumor bed over 4 weeks. She was then treated with seven additional cycles of dactinomycin at 3- to 4-month intervals concluding in 1970. The patient remained well until 1978 when she presented at age 15 years (10 years after

157 diagnosis of Wilms' tumor) with a 2-week history of leg weakness, arthralgias, fever, and malaise. Physical examination revealed diffuse adenopathy and hepatosplenomegaly. Peripheral-blood cell counts disclosed anemia, thrombocytopenia, and a leukocyte count of 16.7 x 109/L with 72% lymphoblasts. Bone marrow aspirate and biopsy were diagnostic of ALL. After 4 weeks of prednisone, vincristine, and asparaginase, the patient did not achieve complete remission. After 3 additional weeks of therapy and the addition of daunorubicin, complete remission was attained. Maintenance therapy was given with daily mercaptopurine and weekly methotrexate; CNS prophylaxis consisting of 24 Gy of radiotherapy to the whole brain, and intrathecal methotrexate was administered. Seven months later the patient relapsed in the bone marrow and spinal fluid. A second marrow and CNS remission was eventually achieved, but the patient died in March 1979 (1 year after the onset of ALL and 11 years after diagnosis of Wilms' tumor) of recurrent ALL. It is noteworthy that the patient's older brother had been diagnosed with Wilms' tumor in 1963 at age 8 months. He was treated with resection and postoperative radiotherapy; no further details of his history are known. He was last examined at our institution in 1978 at age 16 and found to be in excellent health with no evidence of hemihypertrophy, genitourinary or ocular abnormalities, or mental retardation. Case 3. Patient no. 3 presented in 1976 at age 5 years with left cervical adenopathy and was diagnosed with stage IA mixed cellularity Hodgkin's disease. He was treated with 15 Gy of radiotherapy to the left hemimantle and 16 Gy to the upper abdomen, followed by six cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). He was well until January 1985 when he was found to have a thyroid nodule pathologically diagnosed as the follicular variant of papillary thyroid carcinoma (multifocal). He was treated with subtotal thyroidectomy and radioactive iodine followed by thyroid hormone replacement therapy. In September 1985 (9 years after diagnosis of Hodgkin's disease and 8 months after diagnosis of thyroid carcinoma), the patient presented with abdominal fullness and bone pain. Laboratory tests disclosed thrombocytopenia and a leukocyte count of 15.8 x 109/L with 47% lymphoblasts; bone marrow examination confirmed the diagnosis of ALL. Immunophenotyping studies revealed that the blasts expressed the CD10, CD20, and CD24 antigens in addition to HLA-DR, indicative of ALL of early pre-B-cell lineage. The patient was treated with standard ALL therapy of the Pediatric Oncology Group 47 and entered a complete remission. In September 1986, the patient experienced an ontherapy marrow relapse. Remission could not be reinduced, and he died of progressive leukemia in April 1987, 18 months after diagnosis of ALL, 2 years after diagnosis of thyroid carcinoma, and 10.5 years after diagnosis of Hodgkin's disease. RESULTS

To confirm the T-cell lineage and clonality of ALL in patient no. 1, we analyzed the TCR and Ig genes for rearrangements. As shown in Fig 1, there are clonal rearrangements of the beta and gamma TCR genes, but the Ig heavy and light chain genes remain in the germline configuration. Taken together, the results of immunophenotyping and genotyping studies indicate that the lymphocyte proliferation was neoplastic and of T-cell lineage.

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 8, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

158

HUNGER, SKLAR AND LINK

Fig 1. Southern blot autoradiograms of clonal rearrangements of genes in patient no. 1: (A) TCR genes; (B) Ig genes. Arrows indicate the clonal rearranged bands present in the I andy TCR genes, but not in the Ig genes. The sizes of germline DNA bands are shown in kilobase (kb) pairs. The probes and restriction enzymes used for each analysis are indicated above and below, respectively, the autoradiograms.

Our experience with patient no. 1 prompted us to review the experience at the Children's Hospital at Stanford for other cases of ALL as an SMN. This review disclosed two additional patients (patients no. 2 and 3 in this report) who had developed ALL as a second malignancy after Wilms' tumor and Hodgkin's disease. We then reviewed the published literature for other cases of secondary ALL; the results of this review are shown in Table 1 (cases with insufficient data regarding the first malignant neoplasm [FMN] and its therapy were excluded; additional cases are mentioned in Table 2). Including the three patients described in this report, we found a total of 18 patients in whom an FMN was diagnosed in childhood (age < 16 years) and who later developed ALL as an SMN after an interval ranging from 1 to 12 (mean, 5.2) years. The FMNs included Hodgkin's disease (four), Wilms' tumor (four), neuroblastoma (three), ependymoma (two), retinoblastoma (two); and one case each of soft tissue sarcoma, osteosarcoma, and Ewing's sarcoma. The spectrum of FMNs in these patients differs somewhat from the usual distribution observed in childhood, with a preponderance of Wilms' tumor, Hodgkin's disease, and neuroblastoma, and a notable absence of brain tumors. This may represent an ascertainment bias, as only those patients who are cured of their FMNs, or who attain a significant period of disease-free survival, will be at risk for development of second malignancies. Hodgkin's disease and Wilms' tumor have been among the most curable pediatric tumors since the advent of modern chemo/radiotherapy. There are no cases of ANLL or NHL as FMNs because these were specifically excluded (see Materials and Methods). Of the 18 patients described in this report, therapy for the FMN consisted of chemotherapy alone in five

patients, radiation therapy alone in three patients, combined modality therapy in nine patients, and surgery without adjuvant therapy in one patient with retinoblastoma. Of the 14 patients who received chemotherapy, nine were treated with an alkylating agent as part of their therapy and five received no alkylating agents. The latter patients include all four patients with Wilms' tumor and one of the patients with retinoblastoma; each of these patients received dactinomycin with or without vincristine. Recently, the epipodophyllotoxins have been implicated in the development of second malignancies48; four of the patients in this series were treated with etoposide and/or teniposide, each of whom was also exposed to alkylating agents. There are limited cytogenetic data available; however, it is interesting that two of the patients (no. 14 and no. 18) had t(4;11)(q21;q23).38'43 The only other case for which cytogenetic data are available is patient no. 1, in whom no clonal abnormality was detected. DISCUSSION

In this report we describe three patients from our institution with ALL as an SMN. Features of these leukemias indicate that the lineage was clearly lymphoid in each of the three cases. Patient no. 2 developed ALL before the advent of modern immunodiagnostic techniques, but the leukemic cells were classified as lymphoid on the basis of standard morphology and histochemistry. The immunophenotype of patient no. 3 is indicative of early B-cell lineage or common ALL. The most intriguing case is patient no. 1, who developed secondary T-ALL coincident with relapse of neuroblastoma. Several authors have reported metastatic neuroblastoma masquerading as leukemia; however, each of

Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 8, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

159

SECONDARY ALL IN CHILDHOOD t 0

ti 0

.•_

.V• .I•_

o

0

0.

a.

C-4

C.-

"mN o

E

o

-2

"to

t

=D

E

E

t

c

Acute lymphoblastic leukemia occurring as a second malignant neoplasm in childhood: report of three cases and review of the literature.

The long-term effects of childhood cancer and its therapy are a problem of increasing concern. One of the most important of these late effects is the ...
722KB Sizes 0 Downloads 0 Views