Radiation-induced = adult medulloblastoma: a two-case report and review of the = literature

Case Report

Radiation-induced = adult=20 medulloblastoma: a two-case report and review of the literature

Michael D. Chan¹, Albert Attia¹,=20 Stephen B. Tatter², Glenn Lesser³,=20 Michael E. Zapadka⁴, = Ryan T. Mott⁵,=20 Annette Carter¹, = Kevin P. McMullen¹,=20 Edward G. Shaw¹ and=20 Thomas E. Ellis²

(1)

Department of Radiation Oncology, Wake = Forest=20 University Health Sciences=97Baptist Medical Center, 1 Medical = Center Blvd,=20 Winston-Salem, NC 27103, USA

(2)

Department of Neurosurgery, Wake = Forest=20 University Health Sciences, Winston-Salem, NC 27103,=20 USA

(3)

Department of Internal Medicine = (Hematology=20 and Oncology), Wake Forest University Health Sciences, = Winston-Salem,=20 NC 27103, USA

(4)

Department of Radiology, Wake Forest=20 University Health Sciences, Winston-Salem, NC 27103,=20 USA

(5)

Department of Pathology, Wake Forest=20 University Health Sciences, Winston-Salem, NC 27103,=20 USA

Received:=20 1 April 2010 Accepted:=20 25 September 2010 Published = online:=20 9 October 2010

Abstract

Radiation-induced medulloblastoma is an exceedingly = rare=20 phenomenon for which treatment standards have not been established. The=20 literature suggests that these tumors are high grade with aggressive = behavior.=20 We report two cases of radiation-induced medulloblastoma which have been = treated=20 with full dose re-irradiation with curative intent. In both cases, = treatment=20 toxicity and tumor progression proved to be insurmountable obstacles. = Further=20 reports are necessary in order to fully characterize this clinical = entity so=20 that more effective therapies may be sought.

Keywords Radiation-induced=20 malignancy - Medulloblastoma - Re-irradiation

Introduction

Medulloblastoma is a rare tumor that accounts for only = about 1%=20 of adult CNS tumors [1].=20 The treatment paradigm for adult medulloblastoma includes maximal safe=20 resection, radiation therapy, and possibly chemotherapy. = Radiation-induced=20 medulloblastoma poses a more difficult therapeutic dilemma because the=20 surrounding normal brain tissues have often received a full course of=20 radiotherapy. With radiation-induced tumors of other histologies, there = is=20 evidence that being radiation-induced may portend a more aggressive = biology than=20 the non-radiation-induced variants. With sufficient latency between the = prior=20 radiotherapy and the radiation-induced medulloblastoma, definitive = surgery,=20 radiotherapy, and possibly chemotherapy may be considered therapeutic = options.=20 We report two cases of radiation-induced medulloblastoma that occurred = several=20 decades after adjuvant full-dose radiotherapy for craniopharyngioma and=20 low-grade astrocytoma.

Case report 1

The first patient was a 44-year-old woman who had = been=20 diagnosed with craniopharyngioma at the age of 11 years in 1975. = Her=20 original tumor was treated at our institution with maximal safe = resection=20 followed by adjuvant radiation therapy to a total dose of = 5,500 cGy. She=20 remained disease free for over three decades subsequent to her = treatment, though=20 she did develop a moderately shortened stature, as well as = panhypopituitarism=20 and diabetes insipidus that were controlled medically. Her last routine=20 follow-up scan was performed in 2006, and revealed no evidence of tumor=20 recurrence. The patient was able to live independently with her husband, = and=20 maintained a good quality of life until 2008 when she experienced = progressive=20 difficulty with her gait. She subsequently developed memory loss and = somnolence.=20 She sought medical attention with her primary care physician who ordered = an MRI=20 scan of the brain. It revealed a heterogeneously enhancing mass = involving the=20 left cerebral peduncle, the cerebellum, and the pons (Fig. 1a).=20 The patient was referred back to our institution for stereotactic = biopsy.=20

Fig. 1 a=20 Lateral plain film X-ray showing the original RT portal for the adjuvant = treatment of a subtotally resected craniopharyngioma. b Sagittal = MRI,=20 Fluid Attenuated Inversion Recovery (FLAIR) sequence showing the = secondary=20 medulloblastoma to be in the high dose region of the previous RT field. = An=20 estimation of the previous RT field is superimposed onto the current MRI =

Pathology revealed WHO grade IV anaplastic = medulloblastoma=20 that was characterized by dense cellularity, marked nuclear = pleomorphism,=20 nuclear molding, brisk mitotic activity, and abundant apoptotic cell = death=20 (Fig. 2a).=20 Many of the tumor cells also displayed intranuclear cytoplasmic=20 pseudoinclusions. Immunohistochemistry revealed strong and diffuse = staining for=20 synaptophysin and microtubule-associated protein 2 (MAP-2), with = negative=20 staining for glial fibrillary acidic protein (GFAP), S100 protein, and = low=20 molecular weight cytokeratin (Fig. 2b,=20 c; negative stains not shown).=20

Fig. 2 a=20 Anaplastic medulloblastoma (Case 1) demonstrating dense cellularity, = marked=20 nuclear pleomorphism, nuclear molding, and a brisk mitotic rate = (H&E, =D7400).=20 b Immunohistochemical stain for synaptophysin showing strong = cytoplasmic=20 immunoreactivity (=D7400). c Immunohistochemical stain for MAP-2 = showing=20 strong cytoplasmic and nuclear immunoreactivity (=D7400)

Staging of the neuraxis including MRI of the total = spine and=20 CSF cytology were both negative. As the mass involved the brainstem, it = was=20 deemed unresectable. As such, she underwent definitive radiotherapy = including=20 craniospinal irradiation to a dose of 36 Gy. The gross tumor with = margin=20 received a boost dose to 54 Gy using intensity modulated radiation = therapy.=20 Of note, a planning MRI scan done 2 weeks after original diagnostic scan = revealed interval tumor progression both at the predominant mass, as = well as=20 within the biopsy tract (Fig. 3).=20 The patient tolerated the course of radiotherapy with some difficulty, = requiring=20 hospital admission for hypovolemia. After completion of treatment, she=20 experienced an acute decline in mental status and was found on = examination to=20 have an unreactive pupil. Repeat MRI revealed no evidence of = hydrocephalus,=20 herniation or significant tumor progression. The patient failed to = respond to=20 both a trial of steroids and empiric antibiotics for a possible = underlying=20 infection. Her family ultimately placed her in hospice care 1 month = later and=20 she died shortly thereafter.=20

Fig. 3 Coronal MRI,=20 contrast-enhanced FLAIR sequence showing the RT-induced medulloblastoma. = This=20 set of images was taken as part of RT-planning, occurring approximately = 3 weeks=20 after the original diagnostic MRI. In this time interval, the tumor = appeared to=20 seed the biopsy tract, as seen with the enhancing nodularity at the left = vertex=20

Case report 2

The patient was a 46-year-old woman who was = diagnosed with a=20 pilocytic astrocytoma at the age of 5 years. She was treated at an = outside=20 institution with surgery, shunt placement, and adjuvant radiotherapy to = a dose=20 of 2,400 cGy. She was disease free until the age of 20 when she = experienced=20 a recurrence of the astrocytoma. She underwent repeat resection without = further=20 adjuvant therapy. The surgical pathology was again consistent with grade = I=20 astrocytoma. Post-operatively, the patient experienced only mild ataxia, = but=20 otherwise maintained an excellent performance status. She married and = was able=20 to work full-time and raise two children. She remained healthy until = 2008, when=20 she experienced a worsening of her ataxia and a progressive short-term = memory=20 loss. MRI of the brain demonstrated a multilocular cystic mass in the = left=20 posterior fossa with nodular enhancement associated with septations on = the walls=20 of the lateral ventricles, as well as diffuse ventriculomegaly = (Fig. 4).=20 The patient subsequently underwent a biopsy with pathology demonstrating = WHO=20 grade IV anaplastic medulloblastoma. She underwent an MRI of the entire = spine,=20 which revealed diffuse leptomeningeal dissemination. She was then = referred to=20 our institution for therapy. Incidentally, a planning MRI of the brain = performed=20 1 month after the initial diagnostic scan demonstrated progression of = dural and=20 ependymal disease as well as enlarging lesions within the pituitary = region,=20 pineal region and posterior aspect of the medulla. The patient went on = to=20 receive craniospinal irradiation to 4,050 cGy at 150 cGy per = fraction.=20 Her gross brain disease received a boost, bringing the total dose to=20 5,490 cGy. She initially tolerated her therapy well, but = experienced a=20 precipitous decline in performance status and mental status during the = final=20 week of radiotherapy. Imaging revealed persistent hydrocephalus. After=20 completion of radiotherapy, the patient underwent a shunt revision, but = the=20 hydrocephalus was intractable. Her mental status continued to = deteriorate and=20 her family placed her into hospice care where she subsequently died, 2 = weeks=20 after completion of radiotherapy.=20

Fig. 4 Axial=20 post-contrast T1 FLAIR weighted images demonstrate a cystic posterior = fossa mass=20 with peripheral nodular enhancement. These also illustrate diffuse dural = and=20 ependymal enhancement with more focal enhancing masses in the pineal = region and=20 optic chiasm (arrows)

Discussion

Mutations in genes in the Sonic HedgeHog-Patched = pathway appear=20 to predispose to medulloblastoma development [2,=20 3].=20 A preclinical model of radiation-induced medulloblastoma in mice has = been=20 published recently [4].=20 In this report, the authors irradiated mice that were heterozygotes for = a Ptc1=20 gene mutation. These mice developed medulloblastoma whereas the = non-irradiated=20 controls developed only abnormal cerebellar proliferations. It is = hypothesized=20 that the radiotherapy provides the =93second hit=94 genetically in these = mice.=20 Moreover, this hypothesis provides a possible mechanism for = radiation-induced=20 medulloblastoma in humans. A series of radiation-induced gliomas has = been=20 described in which the genetic mutations observed were found to be = similar to=20 those seen in spontaneous gliomas [5].=20

Radiation-induced medulloblastoma is an exceedingly = rare disease=20 entity, with only two cases previously reported in the literature.=20 Radiation-induced medulloblastoma is likely related to radiation-induced = primitive neuroectodermal tumors (PNET), of which there have been = seventeen=20 cases previously reported [6=968].=20 More common radiation-induced brain tumors include meningioma and = glioma. In=20 spite of radiation-induced glioma being a more common entity than=20 radiation-induced medulloblastoma, a recent review of radiation-induced = glioma=20 has cited only 116 reported cases in the world literature [9].=20 As such, radiation-induced medulloblastoma may be rare because of the = fact that=20 adult medulloblastoma or PNET represents a smaller fraction of adult = brain=20 tumors than glioma.

The first reported case of radiation-induced = medulloblastoma=20 occurred in a patient who was 15 years subsequent to cranial = irradiation=20 for low grade astrocytoma [10].=20 The medulloblastoma developed in the temporal lobe contralateral to that = of the=20 glioma. The second report occurred in a patient who had a pineal = germinoma at=20 the age of 20 [11].=20 This patient was treated with definitive radiotherapy to a dose of = 45 Gy,=20 and remained disease free for 8 years until he developed the secondary=20 medulloblastoma adjacent to the high dose treatment volume. Both of the = cases=20 reported herein involve patients who experienced the secondary tumor in = the high=20 dose region of the previous treatment field. In fact, in one of the = patients,=20 the simulation films from the initial treatment fields were still = available=20 (Fig. 1a).=20

Both of the previous cases of radiation-induced = medulloblastoma=20 in the literature were of high-grade large cell histology. Both of our = cases=20 likewise had high-grade large cell histology. Anaplastic large cell=20 medulloblastoma is an entity which has been characterized by large = rounded=20 nuclei, prominent nucleoli, and high mitotic rates [3].=20 Furthermore, immunohistochemical staining generally shows synaptophysin=20 immunoreactivity [12].=20 More recent data suggests that genomic aberrations such as MYC and MYCN=20 amplifications can also have prognostic value [13].=20 While MYC levels were not obtained in the current specimens, both = patients in=20 this report showed classic evidence of diffuse synaptophysin = immunostaining, as=20 well as the aforementioned pathologic hallmarks of anaplastic = medulloblastoma.=20

Though the data are sparse, radiation-induced = medulloblastoma=20 appears to be a very aggressive tumor. Most patients in the literature = with=20 radiation-induced PNET or medulloblastoma have fared poorly with = reported median=20 survival times of only 12 months [6].=20 In our first patient, the tumor had already seeded the biopsy tract in = the=20 interval between the biopsy and the MRI done for radiation planning. In = the=20 second patient, there was also evidence of tumor progression in the 1 = month=20 interval between the patient=92s first diagnostic scan and the planning = scan for=20 radiation therapy.

It should be noted that only one of the previously = reported=20 patients with radiation-induced PNET or medulloblastoma received = re-irradiation=20 with curative intent. Most patients had been previously treated with = full dose=20 radiotherapy, posing a difficult therapeutic dilemma regarding the = lifetime=20 tolerance of the brain to radiotherapy. In the prior case reports, most=20 radiation-induced PNET or medulloblastoma were treated with craniotomy = with=20 tumor resection if possible and chemotherapy consisting of CCNU and/or = PCV=20 [6].=20 Others were treated with palliative intent given a poor performance = status at=20 presentation [11].=20 Our intent with the two patients reported herein was to treat = curatively,=20 including the use of craniospinal irradiation. Our philosophy reflected = the=20 belief that after a prolonged interval, the brain repairs some of the = original=20 damage caused by the first course of radiotherapy [14=9616].=20 Merchant et al. [14]=20 has recently published a series of recurrent ependymoma showing the = feasibility=20 of high dose re-irradiation. Most of the tumors in this series were in = the=20 posterior fossa, and thus treated with significant cumulative brainstem = doses.=20 Unfortunately, brainstem injury represents a catastrophic toxicity as = compared=20 to supratentorial brain injury. The cause of death in our first patient = was=20 likely a brainstem injury as reflected by an unreactive pupil and loss = of=20 respiratory regulation. The differential diagnosis for the cause of = death=20 included tumor progression, cerebral edema, and radiation-induced = brainstem=20 injury. Given the short interval from treatment to patient death, the = former two=20 appear most likely. The second patient died as persistent tumor or = scarring in=20 the ventricles caused an intractable hydrocephalus.

While our experience represents only two isolated = cases, it=20 suggests that radiation-induced medulloblastoma is a disease entity that = may not=20 respond to aggressive re-irradiation, particularly with disseminated = disease.=20 Systemic options including high-dose chemotherapy regimens followed by = stem cell=20 rescue could be considered. There have been several reports of high-dose = chemotherapy in the treatment of relapsed medulloblastoma [17,=20 18],=20 and emerging data on the use chemotherapy regimens without radiotherapy = in the=20 upfront setting [19,=20 20].=20 These generally have included alkylating agents and platinum compounds. = The=20 current Children=92s Oncology Group trial for high risk medulloblastoma = uses an=20 induction regimen of vincristine, etoposide, cyclophosphamide, and = cisplatin=20 with or without high dose methotrexate. While the role of chemotherapy = in adult=20 medulloblastoma is uncertain, several previous pediatric trials have = allowed=20 young adults to participate, and this issue likely requires = consideration in the=20 radiation-induced variant.

Conclusion

Radiation-induced medulloblastoma is a rare, but = highly=20 aggressive tumor. Surgery followed by full-dose radiotherapy may be = considered a=20 possible therapeutic approach. Given prior radiotherapy, however, this = cannot=20 always be optimally accomplished. Further reports are necessary in order = to=20 fully characterize this disease entity.

References

Michael D. Chan
Email:=20 mchan@wfubmc.edu

Herrlinger U, Steinbrecher A, Rieger J, Hau P, = Kortmann RD, Meyermann R, Schabet M, Bamberg M, Dichgans J, = Bogdahn U,=20 Weller M (2005) Adult medulloblastoma: prognostic factors and = response to=20 therapy at diagnosis and at relapse. J Neurol 252:291=96299
3DPubMed=20

Corcoran RB, Scott MP (2001) A mouse model for = medulloblastoma and basal cell nevus syndrome. J Neurooncol=20 53:307=96318
3DChemPort=20

Eberhart CG, Burger PC (2003) Anaplasia and = grading in=20 medulloblastomas. Brain Pathol (Zur, Switz) 13:376=96385
3DCrossRef=20

Pazzaglia S, Tanori M, Mancuso M, Gessi M, = Pasquali E,=20 Leonardi S, Oliva MA, Rebessi S, Di Majo V, Covelli V, Giangaspero = F,=20 Saran A (2006) Two-hit model for progression of medulloblastoma=20 preneoplasia in patched heterozygous mice. Oncogene = 25:5575=965580
3DChemPort=20

Brat DJ, James CD, Jedlicka AE, Connolly DC, = Chang E,=20 Castellani RJ, Schmid M, Schiller M, Carson DA, Burger PC (1999) = Molecular=20 genetic alterations in radiation-induced astrocytomas. Am J Pathol = 154:1431=961438
3DChemPort=20

Hader WJ, Drovini-Zis K, Maguire JA (2003) = Primitive=20 neuroectodermal tumors in the central nervous system following = cranial=20 irradiation: a report of four cases. Cancer 97:1072=961076
3DCrossRef=20

Chen AY, Lee H, Hartman J, Greco C, Ryu JK, = O=92Donnell=20 R, Boggan J (2005) Secondary supratentorial primitive = neuroectodermal=20 tumor following irradiation in a patient with low-grade = astrocytoma. AJNR=20 Am J Neuroradiol 26:160=96162
3DPubMed=20

Brustle O, Ohgaki H, Schmitt HP, Walter GF, = Ostertag=20 H, Kleihues P (1992) Primitive neuroectodermal tumors after = prophylactic=20 central nervous system irradiation in children. Association with = an=20 activated K-ras gene. Cancer 69:2385=962392
3DChemPort=20

Salvati M, Frati A, Russo N, Caroli E, Polli = FM,=20 Minniti G, Delfini R (2003) Radiation-induced gliomas: report of = 10 cases=20 and review of the literature. Surg Neurol 60:60=9667 (discussion = 67)
3DPubMed=20

10.

Howes TL, Buatti JM, Kirby PA, Carlisle TL, = Ryken TC=20 (2006) Radiation induced adult medulloblastoma: a case report. J=20 Neurooncol 80:191=96194
3DPubMed=20

11.

Padma MV, Jacobs M, Kraus G, McDowell P, = Satter M,=20 Adineh M, Mantil J (2004) Radiation-induced medulloblastoma in an = adult: a=20 functional imaging study. Neurol India 52:91=9693
3DChemPort=20

12.

Brown HG, Kepner JL, Perlman EJ, Friedman HS, = Strother DR, Duffner PK, Kun LE, Goldthwaite PT, Burger PC (2000) = =93Large=20 cell/anaplastic=94 medulloblastomas: a Pediatric Oncology Group = Study. J=20 Neuropathol Exp Neurol 59:857=96865
3DChemPort=20

13.

Pfister S, Remke M, Benner A, Mendrzyk F, = Toedt G,=20 Felsberg J, Wittmann A, Devens F, Gerber NU, Joos S, Kulozik A,=20 Reifenberger G, Rutkowski S, Wiestler OD, Radlwimmer B, Scheurlen = W,=20 Lichter P, Korshunov A (2009) Outcome prediction in pediatric=20 medulloblastoma based on DNA copy-number aberrations of = chromosomes 6q and=20 17q and the MYC and MYCN loci. J Clin Oncol 27:1627=961636
3DPubMed=20

14.

Merchant TE, Boop FA, Kun LE, Sanford RA = (2008) A=20 retrospective study of surgery and reirradiation for recurrent = ependymoma.=20 Int J Radiat Oncol Biol Phys 71:87=9697
3DPubMed=20

15.

Bauman GS, Sneed PK, Wara WM, Stalpers LJ, = Chang SM,=20 McDermott MW, Gutin PH, Larson DA (1996) Reirradiation of primary = CNS=20 tumors. Int J Radiat Oncol Biol Phys 36:433=96441
3DChemPort=20

16.

Nieder C, Milas L, Ang KK (2000) Tissue = tolerance to=20 reirradiation. Semin Radiat Oncol 10:200=96209
3DChemPort=20

17.

Dunkel IJ, Boyett JM, Yates A, Rosenblum M, = Garvin JH=20 Jr, Bostrom BC, Goldman S, Sender LS, Gardner SL, Li H, Allen JC, = Finlay=20 JL (1998) High-dose carboplatin, thiotepa, and etoposide with = autologous=20 stem-cell rescue for patients with recurrent medulloblastoma. = Children=92s=20 Cancer Group. J Clin Oncol 16:222=96228
3DChemPort=20

18.

Zia MI, Forsyth P, Chaudhry A, Russell J, = Stewart DA=20 (2002) Possible benefits of high-dose chemotherapy and autologous = stem=20 cell transplantation for adults with recurrent medulloblastoma. = Bone=20 Marrow Transplant 30:565=96569
3DChemPort=20

19.

Grill J, Sainte-Rose C, Jouvet A, Gentet JC, = Lejars=20 O, Frappaz D, Doz F, Rialland X, Pichon F, Bertozzi AI, Chastagner = P,=20 Couanet D, Habrand JL, Raquin MA, Le Deley MC, Kalifa C (2005) = Treatment=20 of medulloblastoma with postoperative chemotherapy alone: an SFOP=20 prospective trial in young children. Lancet Oncol = 6:573=96580
3DChemPort=20

20.

Rutkowski S, Bode U, Deinlein F, Ottensmeier = H,=20 Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, = Kortmann RD, Kuehl J (2005) Treatment of early childhood = medulloblastoma=20 by postoperative chemotherapy alone. N Engl J Med = 352:978=96986
3DChemPort=20