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Rhabdoid Tumor in the Pineal Region: Case Report and Literature Review
Journal Pre-proof Adult atypical teratoid/rhabdoid tumor in the pineal region Case report and literature review Joana Monteiro, Bruno Santiago, Rui Manilha, Catarina Viegas, Ana Oliveira, Manuel Cunha e Sá PII:
S1878-8750(19)32913-4
DOI:
https://doi.org/10.1016/j.wneu.2019.11.075
Reference:
WNEU 13744
To appear in:
World Neurosurgery
Received Date: 23 August 2019 Revised Date:
12 November 2019
Accepted Date: 13 November 2019
Please cite this article as: Monteiro J, Santiago B, Manilha R, Viegas C, Oliveira A, Cunha e Sá M, Adult atypical teratoid/rhabdoid tumor in the pineal region Case report and literature review World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.11.075. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Monteiro Adult atypical teratoid/rhabdoid tumor in the pineal region Case report and literature review
Authors: Joana Monteiroa, Bruno Santiagoa, Rui Manilhaa, Catarina Viegasa, Ana Oliveirab, Manuel Cunha e Sáa
Affiliations: a – Department of Neurosurgery, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal b – Department of Pathology, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal
Corresponding Author: Joana Monteiro M.D.
Department of Neurosurgery, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal
TEL: (+351)212727143 FAX: (+351)212957004 [email protected] Highest academic degrees for all authors: Joana Monteiro, M.D.; Bruno Santiago, M.D.; Rui Manilha, M.D.; Catarina Viegas, M.D.; Ana Oliveira, M.D.; Manuel Cunha e Sá, M.D. Keywords: Teratoid rhabdoid tumor, pineal region, adult Short title: Adult AT/RT in the pineal region 1
Monteiro Introduction Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embrionary tumor.1 It occurs mostly in infancy and is extremely rare in adulthood.2 ATRT can be found anywhere in the CNS but is primarily found in the cerebral hemispheres in adults.1,3,4 Its occurrence in the pineal region is extremely rare. To our knowledge there are only six cases of AT/RT in adults in the pineal region reported so far.5 We report an additional case of AT/RT in the pineal region in an adult with immunohistochemical confirmation. To our knowledge, this is the case with the highest survival rate.
Case description A 41-year-old woman presented with a three weeks history of headache, diplopia and lethargy. She had given birth to a healthy child one month earlier. Her medical records were otherwise irrelevant. Neurological examination disclosed left abducens nerve palsy and bilateral papilledema. A magnetic resonance imaging (MRI) scan documented a round irregular mass with vivid heterogeneous enhancement in the pineal region with supratentorial hydrocephalus (Fig. 1). Cerebrospinal fluid (CSF) was negative for alpha-fetoprotein and placental alkaline phosphatase. An endoscopic third ventriculostomy (ETV) followed by a gross total resection via an infratentorial supracerebellar approach in Concorde position were performed. The lesion appeared as an elastic yellowish mass and was adherent to the adjacent structures. Pathological examination revealed a high-grade malignant neoplasm composed of cells with an epitheloid morphology and abundant connective tissue. Mitotic activity was brisk and tumor necrosis was present (Fig. 2). The tumor showed a polyphenotypic appearance and stained positive for vimentin, synaptophysin and neuron-specific enolase (NSE). The majority of tumor cells also
1
Monteiro stained positive for epithelial membrane antigen (EMA) and actin (Fig. 3a, b). Only few scattered tumor cells expressed glial fibrillary acidic protein (GFAP). Tumor cells showed loss of INI1/SMARCB1 staining (Fig. 3c). Definitive diagnosis confirmed an AT/RT (WHO grade IV). The patient presented a Parinaud’s syndrome and left oculomotor nerve palsy after surgery that progressively recovered. At the last follow-up she had no complains, including no double vision. Post-operative brain MRI showed no residual disease and no other lesions were found in spinal MRI (Figs. 4 and 5). The patient did a PET-CT which was normal and a bone marrow aspiration and biopsy, which were negative. CSF cytology was also negative. She was submitted to neuroaxis radiotherapy and chemotherapy following the European Rhabdoid Registry EU-RHAB. The patient is alive at 31 months after surgery. She is neurologically intact and the latest MRI, done 24 months after surgery, shows no evidence of recurrent tumor.
Discussion AT/RT is a malignant embrionary neoplasm of the CNS with a poliphenotypic presentation.6–9 AT/RT is called “teratoid” because it shows elements of two germ cell layers (ectoderm and mesoderm) but “atypical” since it is otherwise very different from classical teratoid tumors as it lacks divergent tissue development pathognomonic of teratomas.1,10–12 “Rhabdoid” refers to the histological similarity to tumors with skeletal muscle differentiation.10 AT/RT is considered a CNS embryonal tumor grade IV (WHO 2016).13 The accurate incidence of AT/RT is not known, probably due to the fact that it has only recently been considered as a distinct pathology.1,14,15 To date there are approximately 55 cases reported in adults.1,4,9 ATRT affects predominantly adults aged 18 to 45 years with a male-female ratio of 2:1.2,10,16
2
Monteiro Although AT/RT can arise in any location in the CNS, the frontal lobe is the most common location in adults.1,4,17 The occurrence of AT/RT in the pineal region is extremely rare.18,19 To our knowledge, there are six reports of AR/RT in the pineal region in adults.3,5,18–21 Their clinicopathological features along with our case are described in Table 1. The mean age at diagnosis was 30 years. Four patients were female. Almost all cases presented with noncommunicating hydrocephalus at the diagnosis. No patient had leptomeningeal disease at diagnosis and only one showed dissemination later on. Extracranial metastasis occurred in two cases. One of them occurred through the ventriculoperitoneal (VP) shunt.20 Our case reports the highest survival rate. Leptomeningeal dissemination occurs in 15-30% of AT/RT patients and seems lower in adults than in children.1,16,17 It can be seen very early in the disease and is considered an indicator of poor prognosis.7,12,22 Approximately one-third of AT/RTs are disseminated at the time of diagnosis.23 AT/RTs tend to disrupt the blood–brain barrier and may extend into the skull and the galea, reflecting their aggressive behavior.10,24,25 Extracranial metastases are rare.26 MRI is the preferred imaging modality showing heterogeneous isointense signal T1- and T2weighted images with multiple necrotic foci, cysts at the periphery of the tumor and variable contrast enhancement.1,12,16,24 This heterogeneity reflects their poliphenotypic nature. Spectroscopy shows a marked choline peak with reduction or absence of N-acetyl aspartate (NAA) and creatinine.3,27 Histologically, AT/RT is composed of rhabdoid cells juxtaposed to a mixture of mesenchymal, epithelial and primitive neuroepithelial cells.4,9,10,23,28 About 10% of AT/RTs are composed purely of rhabdoid cells.3,28 AT/RT should be considered in the differential diagnosis of aggressive intracranial tumors with ambiguous histologic morphology.22
3
Monteiro AT/RT is characterized by the expression of a broad spectrum of proteins on immunohistochemical reactions, reflecting their poliphenotypic nature.8,28 AT/RT cells are classically positive for vimentin, smooth muscle actin (SMA) and EMA staining but their absence does not exclude the diagnosis.10 Some cells may also demonstrate expression of GFAP, neurofilaments, synaptophysin, NSE, desmin and keratin. Markers for germ cell tumors are consistently negative.18,19 AT/RTs are genetically characterized by inactivating mutations of the INtegrase Interactor 1 (INI1) gene, which is a tumor suppressor gene located at chromosome 22q11.2.10,16 Loss of INI1 protein expression is considered a defining feature of AT/RT and may be sufficient for diagnosis.10,13,29 AT/RT is the only CNS tumor for which a tumor-suppressor gene mutation is pathognomonic.25 However, the absence of this mutation should not exclude the diagnosis.10,14 In rare cases, AT/RT may be defined by alterations of tumor suppressor Brahma-related gene-1 (BRG1).13,23 In the presence of a tumor with histological features of AT/RT but without these mutations, only a descriptive diagnosis of CNS embryonal tumor with rhabdoid features can be made.13 In our case, the tumor didn’t show the most classic rhabdoid cells that are usually seen in AT/RT. Also, the presence of a fibrous desmoplastic background is unusual in AT/RTs. Admittedly, this could be the result of the tumor growing in the pineal region and in part involving the meninges. Even though the histopathological picture was not characteristic of AT/RT, the immunohistochemical staining profile was consistent with this diagnosis. The diagnosis of AT/RT is difficult to determine in adults due to its rarity and poliphenotypic nature and also due to its wide differential diagnosis, so the threshold for investigation with INI1 immunohistochemistry must be low.9,19,22
4
Monteiro ATRT can be divided in three different epigenetic subgroups which comprise different CNS locations and ages of presentation (AT/RT-TYR, AT/RT-SHH and AT/RT-MYC subgroups).1,10,30 We did not perform advanced molecular genetic analysis to assist with the subgroup analysis of the AT/RT, which would have been interesting to correlate with the age of presentation, location and even prognosis. To our knowledge three women with AT/RT were pregnant at the time of diagnosis. The real implication of this association is not known.31 There are no reports about puerperal women diagnosed with AT/RT. Pregnancy may affect tumor growth through hormonal and physiological modulation, such as the insulin-like growth factor I receptor (IGF-IR) signaling pathway.26 AT/RT expresses high levels of IGF-IR which protects tumor cells from apoptosis.32 Treatment options in adults are extrapolated from the pediatric protocols. Gross total resection and combined chemotherapy and cranio-spinal irradiation are the gold-standard treatment in adults.17,33 The extent of resection seems to be a significant predictor of prognosis.10 Approximately half of the tumors are responsive to chemotherapy, but it is rarely curative alone.23 Patients with AT/RT profit from anthracycline based regimens, as the advocated in the European Rhabdoid Registry (EU-RHAB) protocol.28 Encouraging results have been reported with proton therapy, which may be an alternative to classic radiotherapy in younger patients.3,10,16 Stereotactic radiosurgery has been used for recurrent disease when resection is not possible.5 AT/RT has an unfavorable prognosis due to a high rate of local relapse and subarachnoid dissemination.17,29 Survival one year after diagnosis is 39.7% and disease-related death usually occurs within 2 to 20 months after the diagnosis although it has been reported from 2 weeks to 17 years.16 Some studies report long term survival rates and they seem to correlate to supratentorial
5
Monteiro location of the tumor, lower complications of the treatments and adult age at diagnosis.10,16,22,25 Survival time in adults averages 38 months.22,25 This suggests that adult AT/RTs may have a different biological nature or it may simply be related to the fact that adults can tolerate aggressive adjuvant treatments better than young children, for example radiotherapy dosages 16,17,26,34
typically not tolerated by children.
This is particularly true in children under the age of
three, because of the potential negative effects on the developing brain. Also, one can
hypothesize that severe sequelae may not be as accepted in children and therefore some surgeons may operate less aggressively in children.
Conclusion We describe a case of adult AT/RT in the pineal region, which is an extremely rare occurrence. So far, the patient has an impressive overall survival as opposed to the data described in the literature.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts and Interests The authors declare that there is no conflict of interest.
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Monteiro Acknowledgments: Manuela Mafra MD, Department of Pathology, Portuguese Institute of Oncology Francisco Gentil, Lisbon Caterin Giannini MD, Division of Anatomic Pathology, Mayo Clinic, Rochester Prof. Dr. Med Werner Paulus, Institut fur Neuropathologie, Universitatsklinikum Munster, Germany Prof. Dr. Med Martin Hasselblatt, Institut fur Neuropathologie, Universitatsklinikum Munster, Germany
7
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Jin S, Sun C, Yu S, Wang Q, An T, Wen Y. Atypical teratoid/rhabdoid tumor of the brain in an adult with 22q deletion but no absence of INI1 protein: a and review of the literature. Folia Neuropathol. 2015;53(1):80-85. doi:10.5114/fn.2015.49977
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Rorke LB, Packer R, Biegel J. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurooncol. 1995;24:21-28.
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Valencia-Moya A, González-García L, Ros-López B, et al. Prognosis of atypical teratoid rhabdoid tumors (AT/RT) treated with multimodal therapy protocols. Report of our series. Neurocirugia. 2016;27(2):87-94. doi:10.1016/j.neucir.2015.01.003
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Kuge A, Sato S, Sakurada K, Takemura S, Kayama T. Atypical teratoid rhabdoid tumor located in the pineal region following prophylactic irradiation for acute lymphoblastic leukemia. Brain Tumor Pathol. 2012;29:177-181. doi:10.1007/s10014-011-0075-8
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Takei H, Adesina AM, Mehta V, Powell SZ, Langford LA. Atypical teratoid/rhabdoid tumor of the pineal region in an adult. J Neurosurg. 2010;113:374-379. doi:10.3171/2009.10.jns09964
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Ingold B, Moschopulos M, Hutter G, et al. Abdominal seeding of an atypical teratoid/rhabdoid tumor of the pineal gland along a ventriculoperitoneal shunt catheter [2]. Acta Neuropathol. 2006;111:56-59. doi:10.1007/s00401-005-1112-7
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Sugita Y, Takahashi Y, Hayashi I, Morimatsu M, Okamoto K, Shigemori M. Pineal malignant rhabdoid tumor with chondroid formation in an adult. Pathol Int. 1999;49:1114-1118. doi:10.1046/j.1440-1827.1999.00988.x
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Biegel JA, Kalpana G, Knudsen ES, et al. The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: Meeting summary from the workshop on childhood
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Arslanoglu A, Aygun N, Tekhtani D, et al. Imaging Findings of CNS Atypical Teratoid/Rhabdoid Tumors. Am J Neuroradiol. 2004;25:476-480.
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Mirone G, Bouazza S, Chibbaro S, Bresson D, Pavlika M, George B. Primary malignant rhabdoid tumour of the brain in adults. J Clin Neurosci. 2009;16:1495-1497. doi:10.1016/j.jocn.2009.02.011
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Biswas A, Goyal S, Puri T, et al. Atypical teratoid rhabdoid tumor of the brain: Case series and review of literature. Child’s Nerv Syst. 2009;25:1495-1500. doi:10.1007/s00381-009-0903-x
28.
Frühwald MC. European Rhabdoid Registry V2.2010 https://www.skion.nl/workspace/uploads/eurhab_protocol_atrt_versie_15-11-2010.pdf; Accessed 10 September 2018
29.
Park HG, Yoon JH, Kim SH, et al. Adult-Onset Sellar and Suprasellar Atypical Teratoid Rhabdoid Tumor Treated with a Multimodal Approach: A Case Report. Brain Tumor Res Treat. 2014;2(2):108-113. doi:10.14791/btrt.2014.2.2.108
30.
Johann PD, Erkek S, Zapatka M, et al. Atypical Teratoid/Rhabdoid Tumors Are Comprised of Three Epigenetic Subgroups with Distinct Enhancer Landscapes. Cancer Cell. 2016;29:379-393. doi:10.1016/j.ccell.2016.02.001
31.
Erickson ML, Johnson R, Bannykh SI, de Lotbiniere A, Kim JH. Malignant rhabdoid tumor in a pregnant adult female: Literature review of central nervous system rhabdoid tumors. J Neurooncol. 2005;74:311-319. doi:10.1007/s11060-004-7560-4
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Monteiro 32.
D’cunja J, Shalaby T, Rivera P, et al. Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells. Eur J Cancer. 2007;43:1581-1589. doi:10.1016/j.ejca.2007.03.003
33.
Benesch M, Bartelheim K, Fleischhack G, et al. High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): A report from the European Rhabdoid Registry (EU-RHAB). Bone Marrow Transplant. 2014;49:370-375. doi:10.1038/bmt.2013.208
34.
Slavc I, Chocholous M, Leiss U, et al. Atypical teratoid rhabdoid tumor: improved longterm survival with an intensive multimodal therapy and delayed radiotherapy. The Medical University of Vienna Experience 1992-2012. Cancer Med. 2014;3(1):91-100. doi:10.1002/cam4.161
12
Fig. 1 Preoperative MRI T1-weighted images after contrast administration: A round irregular mass with vivid heterogeneous enhancement in the pineal region was noted. a Sagittal view. b Axial view. c Coronal view Fig. 2 Pathological findings: H&E stain showed tumor cells with an epitheloid morphology with prominent nucleoli and high mitotic activity. Original magnification: 400 Fig. 3: Photomicrographs of immunohistochemical findings: a Most tumor cells stained positive for epithelial membrane antigen (EMA). b The majority of tumor cells also stained positive for actin. c Tumor cells showed loss of nuclear INI1 staining with positive internal control (endothelial cells). Original magnification: 400 Fig. 4 Post-operative MRI T1-weighted images after contrast administration: There was no residual disease. a Sagittal view. b Axial view. c Coronal view Fig. 5 Spinal MRI T1-weighted images: there were no other lesions. a Cervical spine, sagittal view. b Thoracic spine, sagittal view. c Lumbar spine, sagittal view
Table 1: Description of the cases of AR/RT in the pineal region in adults reported in the
Radiotherapy
Chemotherapy
Follow-up/
Yes
Alive/31
2017
M
VP shunt
No
No
Near
Yes
Yes
Alive/18
No
Dead/27
Yes
Yes
Alive/18
Partial Yes
Yes
Alive/13
Yes
Yes
Dead/7
Partial Yes
Yes
Dead/24
19
al disease
Liebigt et al 2012
total 20
F
ETV
No
No
Biopsy Gamma
Kuge et al 2011
months
Resection
Yes
dissemination
Total
Extracranial No
Leptomeninge No
s treatment
Hydrocephalu ETV
Age
F
Authors
Present case 41
Year &
Gender
literature, along with our case.3,5,18–21
Knife 33
F
VP shunt
Shonka at al
No
No
(recurrence
Near total
in thalamus and occipital horn) 2010
33
F
VP shunt
Takey et al
No
No
(recurrence in thalamus and occipital horn)
2006
45
F
VP shunt
Ingold et al 1999 Sugita et al
At
Yes (abdomen) Total
recurrence 27
M
No
No
Yes (lung)
Monteiro Abbreviations list: AT/RT - atypical teratoid/rhabdoid tumor BRG1 – Brahma-related gene-1 CNS - central nervous system EMA - epithelial membrane antigen EU-RHAB - European Rhabdoid Registry ETV - endoscopic third ventriculostomy GFAP - glial fibrillary acidic protein H&E - Hematoxylin and eosin IGF-IR - insulin-like growth factor I receptor INI1 - INtegrase Interactor 1 MRI - magnetic resonance imaging NAA - N-acetyl aspartate NSE - neuron-specific enolase SMA - smooth muscle actin VP - ventriculoperitoneal WHO – World Health Organization
1
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S1878-8750(19)32913-4
DOI:
https://doi.org/10.1016/j.wneu.2019.11.075
Reference:
WNEU 13744
To appear in:
World Neurosurgery
Received Date: 23 August 2019 Revised Date:
12 November 2019
Accepted Date: 13 November 2019
Please cite this article as: Monteiro J, Santiago B, Manilha R, Viegas C, Oliveira A, Cunha e Sá M, Adult atypical teratoid/rhabdoid tumor in the pineal region Case report and literature review World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.11.075. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Monteiro Adult atypical teratoid/rhabdoid tumor in the pineal region Case report and literature review
Authors: Joana Monteiroa, Bruno Santiagoa, Rui Manilhaa, Catarina Viegasa, Ana Oliveirab, Manuel Cunha e Sáa
Affiliations: a – Department of Neurosurgery, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal b – Department of Pathology, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal
Corresponding Author: Joana Monteiro M.D.
Department of Neurosurgery, Hospital Garcia de Orta, Avenida Torrado da Silva, 2805-267 Almada, Portugal
TEL: (+351)212727143 FAX: (+351)212957004 [email protected] Highest academic degrees for all authors: Joana Monteiro, M.D.; Bruno Santiago, M.D.; Rui Manilha, M.D.; Catarina Viegas, M.D.; Ana Oliveira, M.D.; Manuel Cunha e Sá, M.D. Keywords: Teratoid rhabdoid tumor, pineal region, adult Short title: Adult AT/RT in the pineal region 1
Monteiro Introduction Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embrionary tumor.1 It occurs mostly in infancy and is extremely rare in adulthood.2 ATRT can be found anywhere in the CNS but is primarily found in the cerebral hemispheres in adults.1,3,4 Its occurrence in the pineal region is extremely rare. To our knowledge there are only six cases of AT/RT in adults in the pineal region reported so far.5 We report an additional case of AT/RT in the pineal region in an adult with immunohistochemical confirmation. To our knowledge, this is the case with the highest survival rate.
Case description A 41-year-old woman presented with a three weeks history of headache, diplopia and lethargy. She had given birth to a healthy child one month earlier. Her medical records were otherwise irrelevant. Neurological examination disclosed left abducens nerve palsy and bilateral papilledema. A magnetic resonance imaging (MRI) scan documented a round irregular mass with vivid heterogeneous enhancement in the pineal region with supratentorial hydrocephalus (Fig. 1). Cerebrospinal fluid (CSF) was negative for alpha-fetoprotein and placental alkaline phosphatase. An endoscopic third ventriculostomy (ETV) followed by a gross total resection via an infratentorial supracerebellar approach in Concorde position were performed. The lesion appeared as an elastic yellowish mass and was adherent to the adjacent structures. Pathological examination revealed a high-grade malignant neoplasm composed of cells with an epitheloid morphology and abundant connective tissue. Mitotic activity was brisk and tumor necrosis was present (Fig. 2). The tumor showed a polyphenotypic appearance and stained positive for vimentin, synaptophysin and neuron-specific enolase (NSE). The majority of tumor cells also
1
Monteiro stained positive for epithelial membrane antigen (EMA) and actin (Fig. 3a, b). Only few scattered tumor cells expressed glial fibrillary acidic protein (GFAP). Tumor cells showed loss of INI1/SMARCB1 staining (Fig. 3c). Definitive diagnosis confirmed an AT/RT (WHO grade IV). The patient presented a Parinaud’s syndrome and left oculomotor nerve palsy after surgery that progressively recovered. At the last follow-up she had no complains, including no double vision. Post-operative brain MRI showed no residual disease and no other lesions were found in spinal MRI (Figs. 4 and 5). The patient did a PET-CT which was normal and a bone marrow aspiration and biopsy, which were negative. CSF cytology was also negative. She was submitted to neuroaxis radiotherapy and chemotherapy following the European Rhabdoid Registry EU-RHAB. The patient is alive at 31 months after surgery. She is neurologically intact and the latest MRI, done 24 months after surgery, shows no evidence of recurrent tumor.
Discussion AT/RT is a malignant embrionary neoplasm of the CNS with a poliphenotypic presentation.6–9 AT/RT is called “teratoid” because it shows elements of two germ cell layers (ectoderm and mesoderm) but “atypical” since it is otherwise very different from classical teratoid tumors as it lacks divergent tissue development pathognomonic of teratomas.1,10–12 “Rhabdoid” refers to the histological similarity to tumors with skeletal muscle differentiation.10 AT/RT is considered a CNS embryonal tumor grade IV (WHO 2016).13 The accurate incidence of AT/RT is not known, probably due to the fact that it has only recently been considered as a distinct pathology.1,14,15 To date there are approximately 55 cases reported in adults.1,4,9 ATRT affects predominantly adults aged 18 to 45 years with a male-female ratio of 2:1.2,10,16
2
Monteiro Although AT/RT can arise in any location in the CNS, the frontal lobe is the most common location in adults.1,4,17 The occurrence of AT/RT in the pineal region is extremely rare.18,19 To our knowledge, there are six reports of AR/RT in the pineal region in adults.3,5,18–21 Their clinicopathological features along with our case are described in Table 1. The mean age at diagnosis was 30 years. Four patients were female. Almost all cases presented with noncommunicating hydrocephalus at the diagnosis. No patient had leptomeningeal disease at diagnosis and only one showed dissemination later on. Extracranial metastasis occurred in two cases. One of them occurred through the ventriculoperitoneal (VP) shunt.20 Our case reports the highest survival rate. Leptomeningeal dissemination occurs in 15-30% of AT/RT patients and seems lower in adults than in children.1,16,17 It can be seen very early in the disease and is considered an indicator of poor prognosis.7,12,22 Approximately one-third of AT/RTs are disseminated at the time of diagnosis.23 AT/RTs tend to disrupt the blood–brain barrier and may extend into the skull and the galea, reflecting their aggressive behavior.10,24,25 Extracranial metastases are rare.26 MRI is the preferred imaging modality showing heterogeneous isointense signal T1- and T2weighted images with multiple necrotic foci, cysts at the periphery of the tumor and variable contrast enhancement.1,12,16,24 This heterogeneity reflects their poliphenotypic nature. Spectroscopy shows a marked choline peak with reduction or absence of N-acetyl aspartate (NAA) and creatinine.3,27 Histologically, AT/RT is composed of rhabdoid cells juxtaposed to a mixture of mesenchymal, epithelial and primitive neuroepithelial cells.4,9,10,23,28 About 10% of AT/RTs are composed purely of rhabdoid cells.3,28 AT/RT should be considered in the differential diagnosis of aggressive intracranial tumors with ambiguous histologic morphology.22
3
Monteiro AT/RT is characterized by the expression of a broad spectrum of proteins on immunohistochemical reactions, reflecting their poliphenotypic nature.8,28 AT/RT cells are classically positive for vimentin, smooth muscle actin (SMA) and EMA staining but their absence does not exclude the diagnosis.10 Some cells may also demonstrate expression of GFAP, neurofilaments, synaptophysin, NSE, desmin and keratin. Markers for germ cell tumors are consistently negative.18,19 AT/RTs are genetically characterized by inactivating mutations of the INtegrase Interactor 1 (INI1) gene, which is a tumor suppressor gene located at chromosome 22q11.2.10,16 Loss of INI1 protein expression is considered a defining feature of AT/RT and may be sufficient for diagnosis.10,13,29 AT/RT is the only CNS tumor for which a tumor-suppressor gene mutation is pathognomonic.25 However, the absence of this mutation should not exclude the diagnosis.10,14 In rare cases, AT/RT may be defined by alterations of tumor suppressor Brahma-related gene-1 (BRG1).13,23 In the presence of a tumor with histological features of AT/RT but without these mutations, only a descriptive diagnosis of CNS embryonal tumor with rhabdoid features can be made.13 In our case, the tumor didn’t show the most classic rhabdoid cells that are usually seen in AT/RT. Also, the presence of a fibrous desmoplastic background is unusual in AT/RTs. Admittedly, this could be the result of the tumor growing in the pineal region and in part involving the meninges. Even though the histopathological picture was not characteristic of AT/RT, the immunohistochemical staining profile was consistent with this diagnosis. The diagnosis of AT/RT is difficult to determine in adults due to its rarity and poliphenotypic nature and also due to its wide differential diagnosis, so the threshold for investigation with INI1 immunohistochemistry must be low.9,19,22
4
Monteiro ATRT can be divided in three different epigenetic subgroups which comprise different CNS locations and ages of presentation (AT/RT-TYR, AT/RT-SHH and AT/RT-MYC subgroups).1,10,30 We did not perform advanced molecular genetic analysis to assist with the subgroup analysis of the AT/RT, which would have been interesting to correlate with the age of presentation, location and even prognosis. To our knowledge three women with AT/RT were pregnant at the time of diagnosis. The real implication of this association is not known.31 There are no reports about puerperal women diagnosed with AT/RT. Pregnancy may affect tumor growth through hormonal and physiological modulation, such as the insulin-like growth factor I receptor (IGF-IR) signaling pathway.26 AT/RT expresses high levels of IGF-IR which protects tumor cells from apoptosis.32 Treatment options in adults are extrapolated from the pediatric protocols. Gross total resection and combined chemotherapy and cranio-spinal irradiation are the gold-standard treatment in adults.17,33 The extent of resection seems to be a significant predictor of prognosis.10 Approximately half of the tumors are responsive to chemotherapy, but it is rarely curative alone.23 Patients with AT/RT profit from anthracycline based regimens, as the advocated in the European Rhabdoid Registry (EU-RHAB) protocol.28 Encouraging results have been reported with proton therapy, which may be an alternative to classic radiotherapy in younger patients.3,10,16 Stereotactic radiosurgery has been used for recurrent disease when resection is not possible.5 AT/RT has an unfavorable prognosis due to a high rate of local relapse and subarachnoid dissemination.17,29 Survival one year after diagnosis is 39.7% and disease-related death usually occurs within 2 to 20 months after the diagnosis although it has been reported from 2 weeks to 17 years.16 Some studies report long term survival rates and they seem to correlate to supratentorial
5
Monteiro location of the tumor, lower complications of the treatments and adult age at diagnosis.10,16,22,25 Survival time in adults averages 38 months.22,25 This suggests that adult AT/RTs may have a different biological nature or it may simply be related to the fact that adults can tolerate aggressive adjuvant treatments better than young children, for example radiotherapy dosages 16,17,26,34
typically not tolerated by children.
This is particularly true in children under the age of
three, because of the potential negative effects on the developing brain. Also, one can
hypothesize that severe sequelae may not be as accepted in children and therefore some surgeons may operate less aggressively in children.
Conclusion We describe a case of adult AT/RT in the pineal region, which is an extremely rare occurrence. So far, the patient has an impressive overall survival as opposed to the data described in the literature.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts and Interests The authors declare that there is no conflict of interest.
6
Monteiro Acknowledgments: Manuela Mafra MD, Department of Pathology, Portuguese Institute of Oncology Francisco Gentil, Lisbon Caterin Giannini MD, Division of Anatomic Pathology, Mayo Clinic, Rochester Prof. Dr. Med Werner Paulus, Institut fur Neuropathologie, Universitatsklinikum Munster, Germany Prof. Dr. Med Martin Hasselblatt, Institut fur Neuropathologie, Universitatsklinikum Munster, Germany
7
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12
Fig. 1 Preoperative MRI T1-weighted images after contrast administration: A round irregular mass with vivid heterogeneous enhancement in the pineal region was noted. a Sagittal view. b Axial view. c Coronal view Fig. 2 Pathological findings: H&E stain showed tumor cells with an epitheloid morphology with prominent nucleoli and high mitotic activity. Original magnification: 400 Fig. 3: Photomicrographs of immunohistochemical findings: a Most tumor cells stained positive for epithelial membrane antigen (EMA). b The majority of tumor cells also stained positive for actin. c Tumor cells showed loss of nuclear INI1 staining with positive internal control (endothelial cells). Original magnification: 400 Fig. 4 Post-operative MRI T1-weighted images after contrast administration: There was no residual disease. a Sagittal view. b Axial view. c Coronal view Fig. 5 Spinal MRI T1-weighted images: there were no other lesions. a Cervical spine, sagittal view. b Thoracic spine, sagittal view. c Lumbar spine, sagittal view
Table 1: Description of the cases of AR/RT in the pineal region in adults reported in the
Radiotherapy
Chemotherapy
Follow-up/
Yes
Alive/31
2017
M
VP shunt
No
No
Near
Yes
Yes
Alive/18
No
Dead/27
Yes
Yes
Alive/18
Partial Yes
Yes
Alive/13
Yes
Yes
Dead/7
Partial Yes
Yes
Dead/24
19
al disease
Liebigt et al 2012
total 20
F
ETV
No
No
Biopsy Gamma
Kuge et al 2011
months
Resection
Yes
dissemination
Total
Extracranial No
Leptomeninge No
s treatment
Hydrocephalu ETV
Age
F
Authors
Present case 41
Year &
Gender
literature, along with our case.3,5,18–21
Knife 33
F
VP shunt
Shonka at al
No
No
(recurrence
Near total
in thalamus and occipital horn) 2010
33
F
VP shunt
Takey et al
No
No
(recurrence in thalamus and occipital horn)
2006
45
F
VP shunt
Ingold et al 1999 Sugita et al
At
Yes (abdomen) Total
recurrence 27
M
No
No
Yes (lung)
Monteiro Abbreviations list: AT/RT - atypical teratoid/rhabdoid tumor BRG1 – Brahma-related gene-1 CNS - central nervous system EMA - epithelial membrane antigen EU-RHAB - European Rhabdoid Registry ETV - endoscopic third ventriculostomy GFAP - glial fibrillary acidic protein H&E - Hematoxylin and eosin IGF-IR - insulin-like growth factor I receptor INI1 - INtegrase Interactor 1 MRI - magnetic resonance imaging NAA - N-acetyl aspartate NSE - neuron-specific enolase SMA - smooth muscle actin VP - ventriculoperitoneal WHO – World Health Organization
1
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: