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ol. 47 ..llR. .0 (. 4J388) . OTIC, C 67574) MI-609, ombina- !C (NSC l vineriv al prcis, Glioblastoma Multiforme Following Prophylactic Cranial Irradiation and Intrathecal Methotrexate in a Child with Acute Lymphocytic Leukemia r incont- lymphotunistraaidazolc- C. K. CHUNG. MD.* JOHN A. STRYKER, MD.* ROBERT CRUSE, 00,t ROBERT VANNUCI. MD,f AND JAVAD TOWFIGHI, MO* irnparing netrika Cases of radiation-induced glioma la humans arc extremely rare. A 2-year-old boy with acute lympho '`tal SoC cytic leukemia had received prophylactic cranial irradiation (2400 rad/2% weeks) and intrathecal methotrexate. Five years later he developed a glioblastoma multiforme on the left cerebral hemisphere i surgical Chic lor mala* n 742 pa- while the leukemia was in remission. This Is the first reported association of these disorders. It is possible that the glioma may have been induced by radiation and/or chemotherapy. Cancer 47:2563-2566, 1981. ici E III. at roela- m treatclan*- lot 4 ini mela- \. Maligihree and <1 1976; A. Bacillc tveKCU iC-332). dy of iso.irv mela 20:313 v (therapy HASCO rapy (Cx) ma with 1 i 20:333 | he institu i ion of specific central nervous system black, tarry stools. Otherwise, he had been healthy. There T prophylaxis when the number of leukemic cells in was no family history of cancer or hereditary disease, includ that location is presumably low has greatly reduced ing Von Recklinghausen's disease. Parents and two siblings occurrence of overt meningeal leukemia, thus increas ing survival of children with acute lymphocytic leukemia.1-" Although the long-term sequelae of central nervous system prophylaxis have not been well defined, the therapeutic modality employed (cranial irradiation and intrathecal chemotherapy) have oc casionally been associated with both acute and delayed neurotoxicity.''*'' One of the most serious complications is a progressive leukoencephalopathy, the clinical were healthy. Physical findings included petechiae in the' buccal mucosa, lymphadenopathy in the neck, epitrochlear and inguinal areas, hepatosplenomegaly, and bruises on both legs. No other skin lesions, dysmorphic features, or anomalies were found. Laboratory findings revealed a hemoglobin 4.9. hematocrit 10.5, platelets 21.000, leukocyte count 68,000 with Wr blasts, 72?f promonocytes, 19/7 lymphocytes without polymorphonuclear, or basophils. The bone marrow aspira tion and biopsy from iliac crest revealed sheets of lympho blasts consistent with the diagnosis of acute lymphocytic manifestation of which includes confusion, somno leukemia. On the second admission he was begun on vincris lence. ataxia, spasticity, seizure, dementia, and more tine 2 mg/M2 intravenously 11.25 my) weekly for six weeks rarely, coma and death. and prednisone 40 my/M1 PO (25 my) daily for six weeks as This case report describes a patient who developed a cerebral glioblastoma five years after prophylactic cranial irradiation and intrathecal methotrexate for an acute lymphocytic leukemia. The particular associa tion of these disorders has not been reported previously. induction. Remission was proven by bone marrow aspiration and physical examination on September 18. 1973. On September 23 he was readmitted for CNS prophylaxis: from September 25 to October 10, 1973, ""cobalt irradiation was given to the whole brain utilizing lateral opposing fields (18 x 12 cm) with a daily dose of 200 rad at the midline. A total tumor dose of Case Report 2400 rad was delivered in 12 fractions over IS elapsed days (981 ret. Nominal Standard Dose). Intrathecal methotrexatc On August 10. 1973. a 2-year-old boy was admitted to the Milton S. Hershey Medical Center of the Pennsylvania Stale I University with a two-week history of tiring easily, fever, and f 12 mg/M1 (7.8 mg) was given twice weekly for six doses. Maintenance therapy was 6-mercaptopurine daily, metho trexate w-cckly. and Cytoxan weekly. Until Janu.il y 1975 Inreceived vincristine and prednisone every three months for three consecutive doses. In February 1975. his icynneit was From the Divisions of 'Radiation Oncology, fNeuropediatrics, and tNeuropathology of The M. S. Hershey Medical Center. The Pennsylvania Stale University. Hershey. Pennsylvania. Address for repnnls: C. K. Chung. Ml). Division of Radiation Oncology, Department of Radiology, M. S. Hershey Medical Center. Hershey PA 17033. Accepted for publication May 21. I9K0. f changed to vincristine and prednisone pulses monthly until August 1976. He continued to receive 6-mercaptopurme daily and met hot re sale weekly until August 1978 At that lime all medication was stopped. He never hud ah exaeetbation and continued to be in remission. lie was readmitted on November 5. Il>78. lot headaches. i IXXW-543X.`lt|,OMII/2563 Ml 75 , Antcnvan l ancer Society i >5(>3 OLI 7073 F 25h4 C.VNC'hR June I 1981 Viil. 41 No. 1 n I * I Jones1 Suena Albert Albert Kosm Fie. I. Histology of the brain tumor. (A, Top* The tumor is highly cellular showing many mitoses, pleomorphic and giant cells. Arrows indicatc entrapped neurons IH Jt E, x 100). tB. Bottom! Well-differentiated reactive astrocytes. Note lack of peroxidase (dark) staining of the tumor cells (PAP immunoperoxidasc prtpsrstko for GFA protein, *250). I j J i i { Son,-" Robin Robin Preis.Pres* A vomiting, and lethargy of three weeks' duration. Physical examination revealed bilateral papilledema, difficulty with speech, and right hemiparesis. A computed tomography (CT) brain scan revealed a large cystic mass in the left parietal area. On November 7,1971, the patient underwent left fronto parietal trephine craniotomy and needle aspiration of a large csstic lesion with xanthochromic contents. Subsequent CT brain scan revealed enlargement of what was thought to be a cystic mass. On December 6. 1978. the patient was readmitted for pro gressive right hemiparesis and headaches. The arteriogram showed hypervascular tumor with suggestion of infiltrating as well as cystic components in left parietal area. On Decem ber 15, 1978, the patient underwent left frontoparietal crani otomy with subsequent resection of highly malignant and infiltrating glioma. Postopcratively the patient was treated with cranial irradiation: 4000 rad/4 weeks to whole brain followed by 1000 rad/1 week to gross tumor with reduced fields. A CT brain scan on March 28. 1979. revealed significant improvement, and the patient initially improved in strength and coordination. However, he became disoriented and lethargic on June I. 1979. His mental and neurologic status became progressively worse. He then had a high temperature and seizures and died on October 15. 1979. Unfortunately, autopsy was not performed. i , J Pathology ,` jThe tissue fragments obtained at surgery were forma- tin fixed and processed for paraffin sectioning. In addi- j tion to routine stains, the sections werealso stained by > peroxidase-antiperoxidase (PAP) method in order to f demonstrate the presence of glial fibrillary acidic (GFA) f pro:* strat Hi plast necr iA). by tl plasi well nucle reacti tumoi On tf gliobl T plas obst bias indt It n unit of c logi den disc OLI 7074 1. 47 No. 11 Glioblastoma following Radiotherapy and Chemotherapy Chung at ul. 2565 . Top) iy misindi- (B, cyte*. of the -pare- Ta>le I. Patients with Glioma following Irradiation (Review of Literature) Authors Jones11 < I960) Saenger" (I960) Albeit1 (1966) Reason for thcrepy - Meningioma (left frontal) Cervicul adenitis Tinea capitis Albeit1 (1966) Tinea capitis Kosmaki1* (1977) Craniopharyngioma Son-(1978) Craniopharyngioma Robinson1* (1978) Robinson1* (1978) Teratoma (pineal) Meningioma Preiuig1* (1979) i Present series Glomus jugular tumor (right middle ear) CNS prophylaxis for acute lymphocytic leukemia * Age at the time of therapy. Age* (years) 33 II 4 10 28 9 10 36 43 2 Radiation Latent dosage period* Sex (rad) (years) Radiation-induced glioma M 4000 M 400 M 300-800 M 300- 800 M 3400 F 6007 M 4000 M 2730 M 4480 M 2400 10 Astrocytoma (right hemisphere! II Glioblastoma 4 Astrocytoma (light optic chiasm) i Astrocytoma (cerebrum) 6 Glioblastoma multiforme (temporal lobe) 3 Malignant astrocytoma (right temporal lobe) 26 Astrocytoma. Grade 4 (right frontal lobe) 21 Astrocytoma. Grade 3 (right temporal lobe) 8 Anaplastic astrocytoma (right cerebellum) 3 Glioblastoma mukiforme deft parietal lobe) t Interval between irradiation and diagnosis. 'uced Meant ongth : and -talus aiurc itely. rma- uidid .I t .FA) protein in the tumor.1* This antigen has been demon strated to be specific for astroglia.4 Histologically the tumor was a highly cellular, ana plastic glial neoplasm with many giant cells, areas of - necrosis, and vascular endothelial proliferation (Fig. IA). The infiltrative nature of the tumor was indicated by the presence of many entrapped neurons in the neo plasm. The PAP method showed the presence of many I well-differentiated astrocytes containing one or two nuclei (Fig. IB). These astrocytes were interpreted as reactive rather than as a part of the neoplasm. The tumor cells did not contain a significant amount of GFA. On the basis of the above findings, the diagnosis of glioblastoma multiforme was made. i Discussion The apparent induction of second malignant neo plasm by antineoplastic therapy is no longer a surprising observation. Though it is impossible to prove, the gliot bl.istoma in this patient was most likely treatment: induced, whether by radiation, chemotherapy, or both, it may have been "spontaneous," although this was unlikely considering the low incidence of glioblastoma of cerebrum in children. The other possibility is a bio logic predisposition to neural crest and neuroecto dermal tumors such as is seen in Von Recklinghausen's disease.11 The negative family history and lack of periph eral manifestations of Von Recklinghausen's disease suggests that it was not a factor in the present case. Radiation-induced brain tumors are well known. Modan et al.*' reported on 11,000 children irradiated for ringworm of the scalp and two matched control groups were followed. Results of this study indicated that the increased risk of head and neck tumors is significant. Most radiation-associated intracranial neoplasms have been primarily sarcoma1111-1* and meningioma.1 T1" um.m-ul The examples of radiation-associated gliomas are rare, although these tumors have been produced experimentally in monkeys121*17 and rats.11' Only a few cases of radiation-associated gliomas in humans have been reported in the literature (Table I): most were male patients with an average age of 15 years (range. 2-43). The radiation dosage ranged from 400-6000 rad with latent period of an average of nine (1-26) years. Although the role of radiation in carcinogenesis has been well established in humans and experimental ani mals.*1" the exact mechanism of radiation-induced car cinogenesis remains to be elucidated. It was demon strated that radiation-induced neoplasm appears to arise through mutagenic capacity and chromosome aberra tion, and the mechanisms leading to neoplastic trans formation involve multistage processes (multihit kinet ics) rather than a single, one-hit type of biochemical alteration. However, too little is known at this time about the cancer process to allow precise and detailed OL1 7075 C'anu r June I !1>HI Vul * siuicmentA concerning mechanisms of carcinogenesis for any human neoplasm. The other possible etiologic factor in induction of this patient's tumor could be the combination of intra thecal methotrexate with cranial irradiation. It is known that administration of methotrexate in combination with 2000 rad or more cranial irradiation may result in multiple necrotic areas with or without gliosis dissemi nated throughout the cerebral white matter (leukoencephalopathy)."'7 However, there is no evidence in man (Table I) or experimental animals to indicate intra thecal methotrexate alone is carcinogenic or that it enhances the carcinogenic effect of radiation. Based on the available evidence there is nothing to indicate that the rare occurrence of the long-term neo plastic hazard or other nonneoplastic complications of radiotherapy and/or chemotherapy in any way out balances the benefits of their use for treatment of acute lymphocytic leukemia. REFERENCES 1. Albert RE. Omran AR. Brauer EW. Follow-up study ofpatients treated by x-ray for tinea capitis. Am J Puh Health 1946: 36:2114--2130. 2. Aur RJA. Husto HO, Verzosa MS ft at: Comparison of two methods of preventing central nervous system leukemia. Blood 1973: 42. 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Cancer 1976: 38:1939-1940. i I f M menu recen again tion.' bladd respd tepa i treatr date tions. men little I nonsi izatioi occur suiting neopli this is recor histo malia Fro Tenne Hospi Sup Natioi Projec A: t Pr tR Ads Patho Act i i Oil 7076