Introduction: Papillary tumors of the pineal region (PTPR) are rare brain tumors characterized by frequent local recurrences. Standardized treatment strategies are not yet defined. Case report: We present the case of a 3-year-old girl diagnosed with PTPR. Due to her young age, adjuvant radiotherapy was omitted after gross total tumor resection. Thirty-six months later, local tumor recurrence occurred. Considering the possible risks of secondary surgery, the recurrent tumor was irradiated with proton radiotherapy. Three months later, the tumor showed near-complete remission. Discussion: Based on this experience and other pediatric case reports from the literature, local radiotherapy might be suggested also after complete tumor resectio

Abela, Lucia

Ares, Carmen

Boltshauser, Eugen

Bozinov, Oliver

Grotzer, Michael

Rushing, Elisabeth

Scheer, Ianina

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CASE REPORTPediatric papillary tumors of the pineal region: to observeor to treat following gross total resection?Lucia Abela & Elisabeth Jane Rushing & Carmen Ares &Ianina Scheer & Oliver Bozinov & Eugen Boltshauser &Michael A. GrotzerReceived: 22 August 2012 /Accepted: 25 September 2012 /Published online: 6 October 2012# Springer-Verlag Berlin Heidelberg 2012AbstractIntroduction Papillary tumors of the pineal region (PTPR)are rare brain tumors characterized by frequent local recur-rences. Standardized treatment strategies are not yet defined.Case report We present the case of a 3-year-old girl diag-nosed with PTPR. Due to her young age, adjuvant radiother-apy was omitted after gross total tumor resection. Thirty-sixmonths later, local tumor recurrence occurred. Consideringthe possible risks of secondary surgery, the recurrent tumorwas irradiated with proton radiotherapy. Three months later,the tumor showed near-complete remission.Discussion Based on this experience and other pediatriccase reports from the literature, local radiotherapy mightbe suggested also after complete tumor resection.Keywords Brain tumor . Child . Proton beam irradiation .OutcomeIntroductionTumors of the pineal region account for about 3–4 % of allbrain tumors in childhood [4]. Papillary tumors of the pinealregion (PTPR) represent a rare and histologically distinct sub-group of tumors originating in this area [3, 10]. First describedby Jouvet et al. in 2003 [10], PTPR have been included in the2007 World Health Organization Classification of Tumors ofthe Nervous System as a separate tumor entity [15]. Among 70PTPR reported to date, examples are recognized in both chil-dren and adults with ages ranging from 5 to 67 years (mean,34 years) [14]. PTPR has a distinctive epithelial character andshows both solid and papillary architecture [6, 10, 14].Immunohistochemical analysis is crucial to distinguish PTPRfrom morphological similar pineal tumors, mainly papillaryependymoma and choroid plexus papilloma [8]. PTPR expressstrong immunoreactivity for CK18, S100, NCAM, neuron-specific enolase (NSE), and vimentin [5, 6]. Due to the specificlocalization of this entity in the region of the posterior com-missure and the distinctive immunohistochemical profile,PTPR is presumed to arise from the specialized ependyma ofthe subcommisural organ [10]. Recent ultrastructural studieshave demonstrated that PTPR has concomitant ependymal,neuroendocrine, and secretory features, lending further supportL. Abela :M. A. GrotzerDepartment of Oncology,University Children’s Hospital of Zurich,Zurich, SwitzerlandE. J. RushingInstitute of Neuropathology, University Hospital of Zurich,Zurich, SwitzerlandC. AresCenter for Proton Therapy, Paul Scherrer Institute,Villigen, SwitzerlandI. ScheerDepartment of Diagnostic Imaging,University Children’s Hospital of Zurich,Zurich, SwitzerlandO. BozinovDepartment of Neurosurgery, University Hospital of Zurich,Zurich, SwitzerlandE. BoltshauserDepartment of Neurology,University Children’s Hospital of Zurich,Zurich, SwitzerlandM. A. Grotzer (*)University Children’s Hospital,Steinwiesstrasse 75,CH-8032 Zurich, Switzerlande-mail: Michael.Grotzer@kispi.uzh.chChilds Nerv Syst (2013) 29:307–310DOI 10.1007/s00381-012-1935-1to this hypothesis [2]. Despite advances in immunohistochem-istry and cytogenetics, the biological behavior of PTPR is stillnot fully understood. Thus, uniform therapeutic guidelineshave not yet been established. Here, we describe a case ofPTPR in a 3-year-old girl with 3.5 years of clinical and neuro-radiological follow-up.Case reportClinical presentationA 3-year-old girl presented to her pediatrician with a history ofnew-onset headaches accompanied by nausea, lasting for sev-eral hours a day. The neurological examination was normal andmigraine was initially suspected. After symptoms persisted for2 weeks, cranial magnetic resonance imaging (MRI) was per-formed. TheMRI revealed a cerebral mass located in the pinealregion measuring 2×2.8×3.5 cm (Fig. 1a). The tumor dis-played dorsal cystic structures and a ventral solid portion withinhomogeneous contrast agent enhancement leading to a com-pression of the tectum. The consecutive aqueductal stenosisresulted in occlusive hydrocephalus. A ventriculostomy of thethird ventricle was performed to reduce intracranial pressure.Tumor markers such as AFP and beta-HCG in serum andcerebrospinal fluid (CSF) were within the normal range. Twoweeks later, the patient underwent gross total tumor resectionthrough a suboccipital supracerebellar approach. Postoperativeimaging demonstrated complete resection (Fig. 1b). On post-operative clinical examination, the girl was found to have avertical supranuclear gaze palsy, convergence deficit, and mid-dilated pupils (Parinaud’s syndrome). This functional deficitled to gait instability, particularly when climbing stairs.Further treatment options were thoroughly discussed.Given the young age of the patient and macroscopically grosstotal tumor resection, the decision was made to omit adjuvantradiotherapy. The girl was followed at 3-month intervals byclinical examinations and cranial MRI. Control intervals wereexpanded to once every 6 months during the second postop-erative year. The clinical course was uneventful, except forpersistent vertical gaze palsy. Local tumor recurrence wasdetected on routine follow-up cranial MRI after 3 years(Fig. 1c). The solid and partially cystic recurrent tumor waslocated within the third ventricle dorsal inferior of the inter-thalamic adhesion without disturbance of the CSF circulation,approximately 1.8×0.7×1.3 cm in size. At this time, thepatient did not show any additional neurological symptoms.The possibility of a second surgery was rejected consideringthe potential risks of additional neurological damage.Subsequently, it was decided to treat the recurrent tumor withproton beam irradiation, with a total dose of 54 Gy (RBE) in30 fractions of 1.8 Gy (RBE) per fraction, five fractions aweek. At first follow-up, 3 months after completion of thera-py, the MRI demonstrated near-complete remission (Fig. 1d).Histological diagnosisHistopathological examination revealed a moderately cellular,epithelial tumor with solid and papillary growth patterns(Fig. 2). Perivascular pseudorosette formation was a promi-nent feature; however, true rosettes could not be demonstrat-ed. The cytoplasm of the neoplastic cells varied from clear toamphophilic. Areas of necrosis were present and mitotic ac-tivity was moderate (4–6/10 HPF). Immunohistochemicalanalysis showed positive cytoplasmic staining for NSE andMAP2, while S100 protein was inhomogeneously expressed.Some tumor cells, mostly those forming papillary structures,displayed positivity for Pan-cytokeratin. Glial fibrillary acidicFig. 1 a Sagittal preoperative T2-weighted MRI showing a cerebralmass with cystic portions located in the pineal region. b Sagittalpostoperative T2-weighted MRI demonstrates complete resection. cLocal tumor recurrence 36 months after complete resection. d AxialT2-weighted MRI obtained after proton beam therapy. A small residualtumor is seen only on axial slices (arrow)Fig. 2 Histopathological features of PTPR demonstrating solid andpapillary growth pattern with perivascular pseudorosette formation308 Childs Nerv Syst (2013) 29:307–310protein immunolabeling was minimal and restricted to peri-vascular areas, particularly adjacent to blood vessels. Stainingfor other neuronal markers like N-Neu, chromogranin A,neurofilament 200, neurofilament 70, and synaptophysinwas negative. The Ki67 proliferation index was up to 10–15 %.DiscussionGrading criteria and therapeutic protocols for PTPR have notyet been established because of the rarity and relatively newdiagnosis in the 2007World Health Organization Classificationof Tumors of the Nervous System. Considering its frequentlocal recurrence, PTPR is thought to correspond at least toWHO grade II/III. To gain further insight into tumor character-istics, genetic analysis has been performed by comparativegenomic hybridization and gene expression studies [7].Losses on chromosome 10 and 22q and gains on chromosomes4, 8, 9, and 12 have been detected. Gene expression analysishas shown upregulation of genes such as ZH4, RFX3, TTRmRNA, and CGRP [5, 8]. Clinical implication of these findingshas not yet been elucidated.Since its original description by Jouvet et al. in 2003,about 70 cases have been reported in literature [14, 16].Among these patients, seven were children under 16 yearsof age (Table 1) [1, 6, 12]. Clinical manifestations includeheadache, diplopia, dizziness, and vomiting [1, 11, 12, 14].Spinal dissemination is rare at the time of diagnosis. A keyfeature of PTPR is their high risk for local recurrence. Threeout of six pediatric patients suffered from local tumor recur-rence, the others were lost to follow-up [1, 6, 12]. Poulgrainet al. investigated the 5-year- and 10-year progression-freesurvival of all reported cases to date, which has been esti-mated at 34.5 and 8.6 %, respectively [14]. Fèvre-Montangeet al. performed univariate analysis to test the prognosticsignificance of clinical variables such as age, gender, tumorsize, gross total tumor resection, and adjuvant radiotherapy[6]. The only clinical factor that tended to be associated withoverall survival and recurrence was the extent of resection[6].Standardization of treatment regimen is not yet determineddue to the lack of reliable clinical and biological predictorsand the small number of cases with careful follow-up.Maximal surgical tumor resection is suggested as the first-line procedure. Radiotherapy and chemotherapy have beenadopted as further treatment options [14]. Radiotherapy hasbeen applied in about two thirds of all reported patients usingdifferent protocols and methods [14]. In the current report,radiotherapywas initially avoided because of the young age ofthe patient and total tumor resection. However, tumor relapseoccurred 3 years after diagnosis, confirming the high risk oflocal recurrence in PTPR. With respect to the apparent highpropensity of local recurrence, adjuvant radiotherapymight beapplied in older children with gross total tumor resection. Inyounger children, the cerebral developmental vulnerabilityhas to be taken into account. However, in case of recurrence,radiotherapy seems to be an effective therapy. Especially inyoung patients, proton beam irradiation needs to be consid-ered in order to reduce the integral dose reduction to theadjacent normal tissue [9, 13, 17, 18].References1. Buffenoir K, Rigoard P, Wager M, Ferrand S, Coulon A, Blanc JL,Bataille B, Listrat A (2008) Papillary tumor of the pineal region ina child: case report and review of the literature. Childs Nerv Syst24:379–3842. Cykowski MD, Wartchow EP, Mierau GW, Stolzenberg ED,Gumerlock MK, Fung KM (2012) Papillary tumor of the pinealregion: ultrastructural study of a case. Ultrastruct Pathol 36:68–773. De Girolami U, Fevre-Montange M, Seilhean D, Jouvet A (2008)Pathology of tumors of the pineal region. Rev Neurol 164:882–8954. Drummond KJ, Rosenfeld JV (1999) Pineal region tumours inchildhood. A 30-year experience. Childs Nerv Syst 15:119–126,discussion 1275. Fevre-Montange M, Champier J, Szathmari A, Wierinckx A,Mottolese C, Guyotat J, Figarella-Branger D, Jouvet A, LachuerJ (2006) Microarray analysis reveals differential gene expressionTable 1 Pediatric patients with PTPR. Treatment modalities and outcomeCase[reference]Age (years) Sex Tumorsize (mm)Operation AdjuvanttherapyFollow-up(months)Recurrence(months)Salvagetherapy1 [12] 1 3/12 M 10 IR CT, RT 15 NA NA2 [6] 5 F 28 CR CT 24 21 CR, RT3 [6] 11 F 30 IR, CR CT, RT 79 72 CR, CT, RT4 [6] 13 M NA CR RT 5 NA NA5 [1] 13 M 31 CR RT 15 NA NA6 [6] 14 M NA CR NA NA NA NA7 [6] 14 M 50 CR CT 102 44, 53, 88 RTNA not available, M male, F female, CR complete resection, IR incomplete resection, CT chemotherapy, RT radiotherapyChilds Nerv Syst (2013) 29:307–310 309patterns in tumors of the pineal region. J Neuropathol Exp Neurol65:675–6846. Fevre-Montange M, Hasselblatt M, Figarella-Branger D, ChauveincL, Champier J, Saint-Pierre G, Taillandier L, Coulon A, Paulus W,Fauchon F, Jouvet A (2006) Prognosis and histopathologic featuresin papillary tumors of the pineal region: a retrospective multicenterstudy of 31 cases. J Neuropathol Exp Neurol 65:1004–10117. Gutenberg A, Brandis A, Hong B, Gunawan B, Enders C, SchaeferIM, Burger R, Ostertag H, Gaab M, Krauss JK, Fuzesi L (2011)Common molecular cytogenetic pathway in papillary tumors of thepineal region (PTPR). Brain Pathol 21(6):672–6778. Hasselblatt M, Blumcke I, Jeibmann A, Rickert CH, Jouvet A, vande Nes JA, Kuchelmeister K, Brunn A, Fevre-Montange M, PaulusW (2006) Immunohistochemical profile and chromosomal imbal-ances in papillary tumours of the pineal region. Neuropathol ApplNeurobiol 32:278–2839. Hug EB (2004) Protons versus photons: a status assessment at thebeginning of the 21st century. Radiother Oncol 73(Suppl 2):S35–3710. Jouvet A, Fauchon F, Liberski P, Saint-Pierre G, Didier-Bazes M,Heitzmann A, Delisle MB, Biassette HA, Vincent S, Mikol J,Streichenberger N, Ahboucha S, Brisson C, Belin MF, Fevre-Montange M (2003) Papillary tumor of the pineal region. Am JSurg Pathol 27:505–51211. Junior GV, Dellaretti M, de Carvalho GT, Brandao RA, Mafra A,de Sousa AA (2011) Papillary tumor of the pineal region. BrainTumor Pathol 28:329–33412. Li J, Recinos PF, Orr BA, Burger PC, Jallo GI, Recinos VR (2011)Papillary tumor of the pineal region in a 15-month-old boy. JNeurosurg Pediatr 7:534–53813. Miralbell R, Lomax A, Bortfeld T, Rouzaud M, Carrie C (1997)Potential role of proton therapy in the treatment of pediatric me-dulloblastoma/primitive neuroectodermal tumors: reduction of thesupratentorial target volume. Int J Radiat Oncol Biol Phys 38:477–48414. Poulgrain K, Gurgo R, Winter C, Ong B, Lau Q (2011) Papillarytumour of the pineal region. J Clin Neurosci 18:1007–101715. Roncaroli F, Scheithauer BW (2007) Papillary tumor of the pinealregion and spindle cell oncocytoma of the pituitary: new tumorentities in the 2007 WHO Classification. Brain Pathol 17:314–31816. Santoro A, D’Elia A, Fazzolari B, Santoro F, Antonelli M,Giangaspero F, Brogna C, Lenzi J, Frati A, Salvati M (2011)Four-year clinical and neuroradiological follow-up of a papillarytumor of the pineal region. Neurol Sci 33(4):931–93517. St Clair WH, Adams JA, Bues M, Fullerton BC, La Shell S, KooyHM, Loeffler JS, Tarbell NJ (2004) Advantage of protons com-pared to conventional X-ray or IMRT in the treatment of a pediatricpatient with medulloblastoma. Int J Radiat Oncol Biol Phys58:727–73418. Yuh GE, Loredo LN, Yonemoto LT, Bush DA, Shahnazi K,Preston W, Slater JM, Slater JD (2004) Reducing toxicity fromcraniospinal irradiation: using proton beams to treat medulloblas-toma in young children. Cancer J 10:386–390310 Childs Nerv Syst (2013) 29:307–310

Pediatric papillary tumors of the pineal region: to observe or to treat following gross total resection?

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Pediatric papillary tumors of the pineal region: to observe or to treat following gross total resection?

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