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Disseminated choroid plexus papillomas in adults: A case series and review of the literature
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Disseminated choroid plexus papillomas in adults: A case series and review of the literature Marwah M. Abdulkader a, Nassir H. Mansour d, Jamie J. Van Gompel e, Gregory A. Bosh b, Edward J. Dropcho c, Jose M. Bonnin a, Aaron A. Cohen-Gadol d,⇑ a
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA c Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA d Department of Neurological Surgery, Indiana University School of Medicine, 340 W 10th Street #6200, Indianapolis, IN 46202, USA e Departments of Neurosurgery and Otolaryngology, Mayo Clinic, Rochester, MN 55905, USA b
a r t i c l e
i n f o
Article history: Received 6 April 2016 Accepted 7 April 2016
Keywords: Adults Choroid plexus papilloma Disseminated
a b s t r a c t Choroid plexus papillomas (CPPs) are uncommon, usually intraventricular, low-grade tumors, accounting for less than 1% of all intracranial neoplasms and 2–4% of brain tumors in children. Dissemination of CPPs to multiple levels of the neuraxis has been seldom observed. Thus far, only 26 adult patients have been reported in the English language literature. With some exceptions, disseminated CPPs have been observed in adults and involved multiple sites along the cerebrospinal fluid pathways. Occasionally, intraparenchymal extension has been documented, and secondary involvement of the suprasellar region has been reported in only five patients. Postoperative treatment of CPPs has not been standardized. Most recommended therapies have been extrapolated from a series of atypical papillomas or carcinomas of the choroid plexus in children. We herein report a series of three patients of disseminated choroid plexus papillomas providing additional insights into this relatively rare entity. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Choroid plexus papilloma (CPP) is a rare primary neuroectodermal tumor of the choroid plexus, accounting for less than 1% of all intracranial neoplasms and 2–4% of brain tumors in children [1]. Histologically, 80% of choroid plexus tumors are papillomas, 15% are atypical papillomas (ACPP), and less than 5% are carcinomas (CPC) [2]. These tumors, in adults, commonly present in the fourth ventricle, arising from the caudal roof with signs and symptoms of hydrocephalus, such as headache, diplopia and ataxia. In children, they are more frequent in the lateral ventricles, particularly in the trigone on the left lateral ventricle [3]. Diffuse craniospinal seeding has been observed in all age groups, and occurs along the entire neuraxis involving the supratentorial, infratentorial compartments and the spine [4]. Extraneural CPPs have been reported. In this study we reviewed 29 cases of disseminated CPPs in individuals older than 18 years of age. In seven of them, the tumor had already metastasized at the time of the original diagnosis while for the remaining 22 patients, including our patients, dissemination occurred subsequent to the initial diagnosis and surgical resection. With some exceptions, disseminated CPPs have been observed in adults and they involve multiple sites along the cerebrospinal fluid (CSF) pathways. Intraparenchymal extension has been documented [5,6]. Remarkably, the metastatic lesions maintain the low-grade features of the primary tumor, a phenomenon that is seen in only a few other central nervous system tumors, including ependymomas. A review of the literature reveals that there is no consensus on the optimal therapeutic approaches to treat disseminated CPPs [7]. The options are somewhat variable and tailored to each individual patient. The prognoses of these patients range from stable disease with long period of symptoms free course, to death within very few ⇑ Corresponding author. Address: Goodman Campbell Brain and Spine, Indiana University, Department of Neurosurgery, 355 W. 16th St. Suite 5100, Indianapolis, IN 46202, USA. Tel.: +1 317 362 8760; fax: +1 317 924 8472. E-mail address: [email protected] (A.A. Cohen-Gadol).
weeks [8]. Recurrence of CPP after gross total resection was reported, but it is rather uncommon. Jeibmann et al. found a recurrence rate of 6% (6 out of 103 patients) for benign CPPs and 29% (6 out of 21) for ACPP [9]. For the majority of patients with CPPs, gross total resection is curative whereas CPCs are more likely to recur and disseminate. The appropriate management of disseminated CPPs has not been proposed. Some authors strongly favor total gross resection in specific cases, while others consider near total resection of the disseminated tumor foci followed by craniospinal axis irradiation a reasonable therapeutic option [10]. Focal radiation and various chemotherapeutic regimens have also been used in disseminated CPPs. Treatment with bevacizumab has previously been used in a case of disseminated CPP and resulted in some relief of the associated painful radiculopathy [11].
2. Materials and methods 2.1. Clinical history 2.1.1. Patient 1 A 38-year-old woman developed episodes of dizziness, headache, some short-term memory impairment, and episodes of confusion. She underwent a craniotomy for resection of a CPP in the right lateral ventricle 19 years earlier. At the time, she had multifocal disease and subtotal gross resection was attempted. Imaging studies obtained prior to that procedure were not available for review. No postoperative radiation or chemotherapy was given as no progression was observed over the subsequent years. She had residual visual field defect. One year later, she developed episodes of dizziness, headache, some short-term memory impairment, and episodes of confusion. MRI of the brain revealed hydrocephalus and multiple intraventricular, and subarachnoid lesions compatible with disseminated CPP (Fig. 1). The tumor masses involved the atrium, body, and temporal horn of the right lateral ventricle as well as the third and fourth
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Fig. 1. Patient 1. (A, B) Axial T1-weighted MRI with contrast, (C–E) sagittal T1 turbo spin-echo (TSE) MRI with contrast, (F) sagittal T2-wighted 3D fluid attenuated inversion recovery (FLAIR) MRI. The patient had resection of a lateral ventricle choroid plexus papilloma (CPP) 1 year previously and subsequent MRI of the brain revealed hydrocephalus and multiple intraventricular and subarachnoid lesions compatible with disseminated CPP.
ventricles. Punctate areas of enhancement were observed in the atrium of the left lateral ventricle. Also noted were areas of enhancement in the right porus acusticus, the left sixth cranial nerve, and the posterior surface of the cerebellar vermis. The largest mass was in the third ventricle, extended into the suprasellar compartment and displaced the optic chiasm. No intraparenchymal lesions could be demonstrated. The large third ventricular/suprasellar lesion was resected via an endoscopic transnasal approach. The details of the surgical procedure have been reported elsewhere [12]. Complete resection of the mass was documented on postoperative imaging. Postoperatively, the patient developed diabetes insipidus and slight worsening of her short-term memory impairment, which partially improved after several months. Follow up MRIs within the year after the surgical resection revealed slow continuous growth of the mass in the right
lateral ventricle while the other lesions remained stable. The patient did not receive any additional adjuvant therapies. 2.1.2. Patient 2 A 50-year-old man presented with oscillopsia, palatal myoclonus and ataxia. Neuroimaging studies revealed a large fourth ventricular lesion as well as multiple tumor nodules in the posterior fossa including in the cerebellopontine angle (CPA) region. He underwent a suboccipital craniotomy and gross total resection of the fourth ventricular tumor and 5 years later he underwent resection of the CPA mass. Twelve years after the initial diagnosis, gamma knife radiosurgery (18 Gy, 24 cm3) was needed to control a fourth ventricular recurrence followed by additional radiosurgery one year later (18 Gy, 0.6 cm3) for multiple nodules in the fourth ventricle and one cervical (C1) spinal metastasis.
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Three years later, whole spine radiotherapy was given for multiple metastases. He underwent ventriculoperitoneal shunting for hydrocephalus four years later and also received gamma knife radiosurgery because of continuous growth of the CPA lesion (14 Gy, 10.2 cm3). Later in his course, a cervical laminectomy was performed to resect three metastatic lesions to the spine. Subsequently, he was treated with temozolomide chemotherapy but there was no evidence of tumor regression. He eventually became wheelchair-bound as a consequence of the disseminated leptomeningeal disease and subsequently died. 2.1.3. Patient 3 A 27-year-old man presented with headache, nausea, and vomiting. He was found to have a tumor in the fourth ventricle, which was resected. Later on, he suffered a recurrence and required subsequent resection, radiation therapy, shunt placement, and gamma knife radiosurgery. Two years later, he was admitted because of acute renal failure. Neuroimaging studies revealed a 10 mm third ventricular/pineal lesion, and multiple fourth ventricular lesions. The patient was treated with radiosurgery (16 Gy, 1.3 cm3) but later expired from unknown causes. 2.2. Pathological findings The tumors in all three patients displayed the classical morphological features of CPPs with complex papillary structures covered by a single layer of cuboidal or low columnar epithelial cells. (Fig. 2) Histopathological examination of tissue from patient 1 revealed the typical pattern of CPP, with no signs of atypia or mitoses. Dense fibrosis with prominent hyalinization was observed in large areas of the mass. In some foci, the stroma resembled amyloid deposits, but staining with Congo red did not confirm this impression. Many of the tumor cells displayed a prominent granular cytoplasm. Occasional foci of calcification were observed. Immunohistochemical analysis was performed on tissue from Patient 1. The tumor cells were diffusely positive for transthyretin
(pre-albumin) and S100 protein. (Fig. 3) Many of the tumor cells, particularly those with a granular cytoplasm, were strongly positive for glial fibrillary acidic protein (GFAP). In many foci, GFAP positivity was observed only on the apical surface of the cells. The tumor cells were negative for cytokeratins 7 and 20 and for epithelial membrane antigen. Only a few foci contained cells positive for p53. The Ki-67 labeling index was generally low (1%). In patient 2, the proliferative indices from each of the multiple resections were compared and showed a steady increase in Ki-67 labeling index from 1.7%, to 6.0–8.5% and 9.1%, respectively. This increase in the proliferation index correlates with the clinically documented progressive increase in the aggressive behavior of the tumor.
3. Discussion CPPs are low grade tumors classified as grade I in the World Health Organization (WHO) grading scheme. They are usually treated with surgical resection alone. Dissemination of CPPs to multiple levels of the neuraxis has been observed in all age groups [13]. In the metastatic foci, the tumors usually retain distinctly low-grade histological characteristics. In most patients the pattern of spread can be traced along the CSF pathways. In this review, we analyzed cases of disseminated CPPs reported since 1961. Only adult patients, 18 years or older, were included in the review (Table 1). All patients had the diagnosis of CPP at the time of their initial presentation. Patients with the diagnoses of ACPP or CPC were excluded. In most patients, the primary lesion developed in the posterior fossa, usually in the fourth ventricle and in the CPA [14–18]. In seven patients, the tumors had already disseminated at the time of original diagnosis. Histopathologically, the metastatic lesions had the same morphological appearance (CPP, WHO grade I) as those of the primary site in 19 patients. In four patients, the secondary lesions had features of ACPP; and in two instances, the metastatic tumors were diagnosed as CPCs.
Fig. 2. Choroid plexus papilloma. (A) Intraoperative cytologic preparation, Hematoxylin and eosin (H&E) 20. (B, D) Tumor with the classical papillary architecture, H&E 100 and 400, (C) foci of dense fibrosis and hyalinization, H&E 100.
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Fig. 3. Choroid plexus papilloma. Immunohistochemical stains, (A) Transthyretin 400, (B) glial fibrillary acidic protein 400, (C) S100 protein 400, (D) p53 400.
The age of the patients ranged between 19 and 58, with a mean age of 38 years. Females represented 55.2% of the patients. The clinical presentation was variable. Over one-half of the patients, (55.2%) presented with headache, dizziness, and hydrocephalus; visual impairment was the initial presentation in 13.8% of patients. The most common site of origin was the fourth ventricle (75.9%) followed by the CPA (10.3%). Local recurrence was more frequent than metastasis to other sites (34.5%). The most common site of metastasis was to the leptomeninges (27.6%) and the suprasellar region (17.24%), respectively. The time span between initial diagnosis and the diagnosis of distant dissemination varied. It was 5 years or longer in 14 patients, while seven patients had evidence of dissemination at the time of first diagnosis. Interestingly, in the majority of the patients (65.5%) the metastatic tumors had the same WHO grade as in the primary lesion. Of all tumors, 62.1% were treated with gross total resection, 31.0% with subtotal resections, and 17.2% of patients were treated with radiation therapy after the surgical resection. In some reports, the metastatic tumors were synchronous with tumor recurrence at the primary site [19]. It is generally accepted that gross total resection is curative, and that even subtotal resections may lead to very good long-term outcomes (Safaee et al.) [20,21]. In this review, most patients had either total or subtotal resection of the primary tumor and dissemination was most often observed in patients who had macroscopically complete resections of their lesions. In most patients, the tumors that eventually became disseminated were diagnosed at age 30 years or later, and they were slightly more frequent in females than in males. It has been standard practice to treat CPPs with surgery alone and other treatment modalities (radiation therapy, chemotherapy) are given in cases of local recurrences, or metastatic disease [22,23]. It is not known whether adjuvant therapies and surgical resection can either delay, or prevent the development of metastatic CPP along the neuraxis [24,25]. Distant spread can be subdivided into three different types: diffuse leptomeningeal seeding involving drop metastasis, intraparenchymal involvement and intraventricular lesions [25–29].
Immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) analyses of non-neoplastic choroid plexus epithelial tissue show expression of both vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor (VEGF) ligands. This phenomenon may suggest a potential value of anti-VEGF therapy for disseminated choroid plexus tumors [11]. Other molecular pathways have also been described in the development of choroid plexus tumors including the activation platelet-derived growth factor receptor (PDGFR) and Notch 3 signaling pathways [30]. The response of choroid plexus epithelial lines expressing PDGFR-beta to imatinib, commonly used to treat chronic myelogenous leukemia, suggests the potential benefit from targeting PDGFR in CPPs with high PDGF expression [11]. Over the last decade, there has been an increasing use of molecular and immunohistochemical markers in the assessment and management of neoplasms in general. Some molecular signatures are used diagnostically to help pathologists classify tumors, whereas others are used to estimate prognosis. Most crucial, are those markers that are used to predict response to certain therapies. For example, CD117 (ckit) has been proposed as a predictive marker in CPP prognosis. We performed this stain in our case but it was non-immunoreactive. In addition, Notch 3 signaling initiates choroid plexus tumor formation. Another locus is the p53 gene. Li-Fraumeni syndrome was described as a condition associated with germline TP53 mutation that is associated with CPC. Tabori et al. showed that somatic TP53 mutation were seen in 50% of CPC, and in only 5% of CPP. Absence of TP53 dysfunction was associated with a favorable prognosis [31]. It is likely that further molecular studies may be helpful in subgrouping/characterizing patients with CPP and offer an opportunity toward improving the accuracy of risk stratification as well as the development and implementation of more effective molecularly targeted therapies. Identification of new markers might refine the current grading scheme, and provide improved insight towards predicting which tumors will be prone to disseminate or recur.
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Table 1 Disseminated choroid plexus papilloma. Reported cases in adults (18 years and older) in the literature Age Gender Symptoms
Site
Metastasis
Time to dissemination
Diagnoses initial/ metastases
Treatment of primary tumor(s)
Wilkins and Rutledge, 1961 [5] Leys et al., 1986 [19] Girardot et al., 1990 [14] Domingues et al., 1991 [13]
56 y 40 y 30 y 35 y
4th ventricle 4th ventricle Cisterna magna Foramen magnum
Cerebellum Lateral ventricle; local recurrence 4th ventricle; local recurrence Spinal leptomeninges
Gross total resection Gross total resection Surgery Subtotal resection
Cerebellopontine angle 4th ventricle
Right temporal lobe; basal cistern
5y 9y 5y Present at time of initial diagnosis Present at time of initial diagnosis 6y
CPP/NA CPP/CPP CPP/NA CPP/CPP CPP/CPP
Subtotal resection
Niikawa et al., 1993 [25]
Hydrocephalus NA NA Facial twitching and radicular leg pain 46 y Female Subconjunctival hemorrhage 38 y Male Nausea, blurred vision
CPP/CPC
Gross total resection
Shakespeare et al., 1997 [10]
27 y Female Neck pain and headache
4th ventricle
3y
CPP/CPP
Subtotal resection
Leblanc et al., 1998 [3]
19 y Female Hydrocephalus
4th ventricle
Present at time of initial diagnosis 5y 2–4 y
CPP/CPP
Gross total resection
CPP/NA CPP/ACPP
Gross total resection; radiation therapy Subtotal resection
8y 4y
CPP/CPP CPP/CPP
Gross total resection Subtotal resection; radiation therapy
5y
CPP/CPP
Gross total resection
Present at time of initial diagnosis 2.5–5 y
CPP/CPP
Subtotal resection
CPP/CPP
Gross total resection
8y
CPP/CPP
Surgery
19 y 1 month
CPP/ACPP CPP/CPP
Gross total resection Subtotal resection
Craniospinal leptomeninges; local 5y recurrence Middle cranial fossa; spinal leptomeninges 4 y
CPP/CPP
Gross total resection
CPP/ACPP
Subtotal resection
Cerebellopontine angle; cranial leptomeninges 3rd ventricle; lateral ventricle Multifocal at presentation
16 y
CPP/CPP
Gross total resection
4y Present at time of initial diagnosis
CPP/ACPP/CPC CPP/CPP
Gross total resection Gross total resection
Multifocal at presentation
Present at time of initial diagnosis
CPP/ACPP
Radiosurgery; gross total resection
Spinal leptomeninges
5 months
CPP/NA
Gross total resection
Enomoto et al., 1991 [16]
Talacchi et al., 1999 [17] Valencak et al., 2000 [28]
Male Male Female Female
Irsutti et al., 2000 [18] Jagielski et al., 2001 [22]
38 y Male Unsteady gait 33 y Female Headache, dizziness and visual impairment 48 y Female Hydrocephalus 50 y Male Hydrocephalus
McEnvoy et al., 2002 [7]
51 y Male
Hesse et al., 2002 [1]
38 y Male
Hydrocephalus
th
4 ventricle, 4th ventricle
Suprasellar region; local recurrence 3rd ventricle; spinal leptomeninges; local recurrence 4th ventricle Suprasellar region; local recurrence 3rd and 4th ventricles Temporal lobe, cerebellum, craniospinal leptomeninges; local recurrence Craniospinal leptomeninges; suprasellar 4th ventricle region Craniospinal leptomeninges 4th ventricle
McCall et al., 2006 [4]
Headache, nausea and vomiting. 22 y Female Hydrocephalus
McCall et al., 2006 [4]
30 y Female Neck pain and dizziness
4th ventricle
Yu et al., 2006 [6] Jinhu et al., 2007 [23]
Posterior fossa 4th ventricle
Ortega-Martinez et al., 2007 [26] Menon et al., 2010 [24]
30 y Male NA 32 y Female Vertigo and intermittent headache 20 y Female Progressive palsy and paresthesia in leg 43 y Male NA
Al-Abdullah et al., 2011 [15]
35 y Male
Dhillon et al., 2012 [2] Peyre et al., 2012 [27]
Headaches and blurred vision 53 y Female Headaches 46 y Female Unsteady gait, hearing loss and facial weakness
Peyre et al., 2012 [27]
39 y Female Facial numbness
Anderson et al., 2013 [11]
58 y Male
Pain in lower extremities
Spinal leptomeninges; cerebellopontine angle; suprasellar region Craniospinal leptomeninges; cerebellum; local recurrence Craniospinal leptomeninges
4th ventricle
4th ventricle Cerebellopontine angle 4th ventricle Lateral ventricle 4th ventricle; cerebellopontine angle; cavernous sinus; frontotemporal region 4th ventricle; Meckel’s cave; prepontine cistern 4th ventricle
Spinal leptomeninges; suprasellar region; local recurrence Craniospinal leptomeninges; local recurrence Spinal leptomeninges Spinal extramedullary subdural mass
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References
153
A large collaborative multi-institutional study may be needed to look at the complex molecular pathways involved in the tumorigenesis of the choroid plexus in order to produce meaningful progress in the treatment of this disease. Possible potential prognostic immunohistochemical markers such as TP53, CD117, VEGF and CD44, SV40 and polyoma viruses JC virus and BK virus, may allow the identification of the invasive potential and predict the propensity for dissemination, metastasis, and tumor behavior. Identification of such markers would help clinicians in designing better individualized treatment regimens, and may encourage the use of more aggressive treatment options during the initial course of CPP, despite its primary low-grade histological features.
Gross total resection and gamma knife radiosurgery, temozolomide Gross total resection and gamma knife radiosurgery
Gross total resection
Subtotal resection
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CPP/CPP
CPP/CPP
References
4th ventricle New Case 3
New Case 2
ACPP = atypical choroid plexus papilloma, CPC = choroid plexus carcinoma, CPP = choroid plexus papilloma, NA = not available, y = years.
CPP/CPP New Case 1
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Present at time of initial diagnosis 25 y 4th ventricle
8y
17 y
Lateral, 3 and 4 ventricles; suprasellar region; cranial leptomeninges Posterior fossa masses, cerebellopontine angle, spinal leptomeninges 3rd ventricle, pineal region and 4th ventricle
th
Craniospinal leptomeninges Zachary et al., 2014 [29]
21 y Female Headache and visual changes 38 y Female Short-term memory loss and headaches 50 y Male Oscillopsia, palatal myoclonus and ataxia 27 y Male Headache, nausea and vomiting
4th ventricle; leptomeninges Lateral ventricle
rd
CPP/CPP
Conflicts of Interest/Disclosures
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[25] Niikawa S, Ito T, Murakawa T, et al. Recurrence of choroid plexus papilloma with malignant transformation. Neurol Med Chir (Tokyo) 1993;33:32–5. [26] Ortega-Martinez M, Cabezudo-Artero JM, Fernandez-Portales I, et al. Diffuse leptomeningeal seeding from benign choroid plexus papilloma. Acta Neurochir (Wien) 2007;149:1229–36 [discussion 1236–7]. [27] Peyre M, Bah A, Kalamarides M. Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 2012;154:295–9. [28] Valencak JB, Dietrich W, Raderer M, et al. Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma. J Neurooncol 2000;49:263–8.
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http://dx.doi.org/10.1016/j.jocn.2016.04.002
Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition Stylianos Pikis a, Yakov Fellig b, Emil Margolin c,⇑ a
Department of Neurosurgery, ‘‘Korgialenio Benakio” Red Cross Hospital of Athens, Athens 11526, Greece Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, Israel c Department of Neurosurgery, Hadassah–Hebrew University Medical Center, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel b
a r t i c l e
i n f o
Article history: Received 8 April 2016 Accepted 12 April 2016
Keywords: Biology Cerebellar liponeurocytomas Familial Inheritance
a b s t r a c t There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Cerebellar liponeurocytoma is defined by the World Health Organization (WHO) as a rare, WHO grade II, cerebellar neoplasm of adults with consistent neuronal, variable astrocytic and focal lipomatous differentiation, and with a low proliferative potential [1]. The genetic origins of this rare entity are yet to be defined and to the best of our knowledge there has been only one report on cerebellar liponeurocytoma affecting different members of the same family [2]. We report a 72-year-old woman with cerebellar liponeurocytoma whose sister was treated in our department for a similar lesion and briefly review the available literature on the molecular biology and histopathologic abnormalities associated with cerebellar liponeurocytomas.
from the right cerebellar hemisphere and compressing the brainstem and fourth ventricle. The lesion was composed of a contrast enhancing superior component and an inferior component exhibiting fat signal (Fig. 1a). Her family history was significant for a sister who underwent partial resection of a cerebellar liponeurocytoma followed by postoperative radiosurgery due to residual tumor enlargement. Six years following operation this patient was asymptomatic without any evidence of tumor recurrence. The current patient underwent sub-occipital craniotomy and gross total resection of a soft, greyish, exophytic, easily dissected tumor. Mild improvement of her symptoms was noted postoperatively and she was discharged to a rehabilitation center. At the 3-year follow-up the patient was asymptomatic without evidence of tumor recurrence on brain MRI (Fig. 1b). 3. Histopathology report
2. Case report A 72-year-old woman was admitted to our clinic due to a posterior fossa space occupying lesion diagnosed by non-contrast head CT scan obtained during head trauma evaluation following a fall. She complained of a 5-month history of progressive headache, unsteadiness, and recurrent falls. Past medical history was significant for untreated hyperthyroidism which was managed pre-operatively. On neurological examination she had ataxia, a tendency to fall on the right, and bilateral dysdiadochokinesia, dysmetria, and intention tremor, worse on the right. Brain MRI revealed a 48 43 41 mm, intra-axial, exophytic lesion arising ⇑ Corresponding author. Tel.: +972 2 677 7092; fax: +972 2 643 1740. E-mail address: [email protected] (E. Margolin).
The neoplasm of the current patient (Fig. 2I–P) displayed typical morphological features of liponeurocytoma, that is, a highly cellular neoplasm, with extensive ‘‘lipomatous” differentiation, infiltrating the cerebellar parenchyma. Occasional rosettes and areas with a prominent vascular network were evident. Most neoplastic cells were relatively uniform, with round or oval nuclei, with finely dispersed chromatin, and clear or pale cytoplasm. There was no necrosis or microvascular proliferation and the MIB-1 proliferation index was 1–3%. In contrast, the neoplasm of her sister (Fig. 2A–H) displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance, focal increased mitotic activity (up to six mitotic figures/10 high-power microscopic fields) and relatively high MIB-1 proliferation index (10–15%), as well as occasional
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Disseminated choroid plexus papillomas in adults: A case series and review of the literature Marwah M. Abdulkader a, Nassir H. Mansour d, Jamie J. Van Gompel e, Gregory A. Bosh b, Edward J. Dropcho c, Jose M. Bonnin a, Aaron A. Cohen-Gadol d,⇑ a
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA c Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA d Department of Neurological Surgery, Indiana University School of Medicine, 340 W 10th Street #6200, Indianapolis, IN 46202, USA e Departments of Neurosurgery and Otolaryngology, Mayo Clinic, Rochester, MN 55905, USA b
a r t i c l e
i n f o
Article history: Received 6 April 2016 Accepted 7 April 2016
Keywords: Adults Choroid plexus papilloma Disseminated
a b s t r a c t Choroid plexus papillomas (CPPs) are uncommon, usually intraventricular, low-grade tumors, accounting for less than 1% of all intracranial neoplasms and 2–4% of brain tumors in children. Dissemination of CPPs to multiple levels of the neuraxis has been seldom observed. Thus far, only 26 adult patients have been reported in the English language literature. With some exceptions, disseminated CPPs have been observed in adults and involved multiple sites along the cerebrospinal fluid pathways. Occasionally, intraparenchymal extension has been documented, and secondary involvement of the suprasellar region has been reported in only five patients. Postoperative treatment of CPPs has not been standardized. Most recommended therapies have been extrapolated from a series of atypical papillomas or carcinomas of the choroid plexus in children. We herein report a series of three patients of disseminated choroid plexus papillomas providing additional insights into this relatively rare entity. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Choroid plexus papilloma (CPP) is a rare primary neuroectodermal tumor of the choroid plexus, accounting for less than 1% of all intracranial neoplasms and 2–4% of brain tumors in children [1]. Histologically, 80% of choroid plexus tumors are papillomas, 15% are atypical papillomas (ACPP), and less than 5% are carcinomas (CPC) [2]. These tumors, in adults, commonly present in the fourth ventricle, arising from the caudal roof with signs and symptoms of hydrocephalus, such as headache, diplopia and ataxia. In children, they are more frequent in the lateral ventricles, particularly in the trigone on the left lateral ventricle [3]. Diffuse craniospinal seeding has been observed in all age groups, and occurs along the entire neuraxis involving the supratentorial, infratentorial compartments and the spine [4]. Extraneural CPPs have been reported. In this study we reviewed 29 cases of disseminated CPPs in individuals older than 18 years of age. In seven of them, the tumor had already metastasized at the time of the original diagnosis while for the remaining 22 patients, including our patients, dissemination occurred subsequent to the initial diagnosis and surgical resection. With some exceptions, disseminated CPPs have been observed in adults and they involve multiple sites along the cerebrospinal fluid (CSF) pathways. Intraparenchymal extension has been documented [5,6]. Remarkably, the metastatic lesions maintain the low-grade features of the primary tumor, a phenomenon that is seen in only a few other central nervous system tumors, including ependymomas. A review of the literature reveals that there is no consensus on the optimal therapeutic approaches to treat disseminated CPPs [7]. The options are somewhat variable and tailored to each individual patient. The prognoses of these patients range from stable disease with long period of symptoms free course, to death within very few ⇑ Corresponding author. Address: Goodman Campbell Brain and Spine, Indiana University, Department of Neurosurgery, 355 W. 16th St. Suite 5100, Indianapolis, IN 46202, USA. Tel.: +1 317 362 8760; fax: +1 317 924 8472. E-mail address: [email protected] (A.A. Cohen-Gadol).
weeks [8]. Recurrence of CPP after gross total resection was reported, but it is rather uncommon. Jeibmann et al. found a recurrence rate of 6% (6 out of 103 patients) for benign CPPs and 29% (6 out of 21) for ACPP [9]. For the majority of patients with CPPs, gross total resection is curative whereas CPCs are more likely to recur and disseminate. The appropriate management of disseminated CPPs has not been proposed. Some authors strongly favor total gross resection in specific cases, while others consider near total resection of the disseminated tumor foci followed by craniospinal axis irradiation a reasonable therapeutic option [10]. Focal radiation and various chemotherapeutic regimens have also been used in disseminated CPPs. Treatment with bevacizumab has previously been used in a case of disseminated CPP and resulted in some relief of the associated painful radiculopathy [11].
2. Materials and methods 2.1. Clinical history 2.1.1. Patient 1 A 38-year-old woman developed episodes of dizziness, headache, some short-term memory impairment, and episodes of confusion. She underwent a craniotomy for resection of a CPP in the right lateral ventricle 19 years earlier. At the time, she had multifocal disease and subtotal gross resection was attempted. Imaging studies obtained prior to that procedure were not available for review. No postoperative radiation or chemotherapy was given as no progression was observed over the subsequent years. She had residual visual field defect. One year later, she developed episodes of dizziness, headache, some short-term memory impairment, and episodes of confusion. MRI of the brain revealed hydrocephalus and multiple intraventricular, and subarachnoid lesions compatible with disseminated CPP (Fig. 1). The tumor masses involved the atrium, body, and temporal horn of the right lateral ventricle as well as the third and fourth
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Fig. 1. Patient 1. (A, B) Axial T1-weighted MRI with contrast, (C–E) sagittal T1 turbo spin-echo (TSE) MRI with contrast, (F) sagittal T2-wighted 3D fluid attenuated inversion recovery (FLAIR) MRI. The patient had resection of a lateral ventricle choroid plexus papilloma (CPP) 1 year previously and subsequent MRI of the brain revealed hydrocephalus and multiple intraventricular and subarachnoid lesions compatible with disseminated CPP.
ventricles. Punctate areas of enhancement were observed in the atrium of the left lateral ventricle. Also noted were areas of enhancement in the right porus acusticus, the left sixth cranial nerve, and the posterior surface of the cerebellar vermis. The largest mass was in the third ventricle, extended into the suprasellar compartment and displaced the optic chiasm. No intraparenchymal lesions could be demonstrated. The large third ventricular/suprasellar lesion was resected via an endoscopic transnasal approach. The details of the surgical procedure have been reported elsewhere [12]. Complete resection of the mass was documented on postoperative imaging. Postoperatively, the patient developed diabetes insipidus and slight worsening of her short-term memory impairment, which partially improved after several months. Follow up MRIs within the year after the surgical resection revealed slow continuous growth of the mass in the right
lateral ventricle while the other lesions remained stable. The patient did not receive any additional adjuvant therapies. 2.1.2. Patient 2 A 50-year-old man presented with oscillopsia, palatal myoclonus and ataxia. Neuroimaging studies revealed a large fourth ventricular lesion as well as multiple tumor nodules in the posterior fossa including in the cerebellopontine angle (CPA) region. He underwent a suboccipital craniotomy and gross total resection of the fourth ventricular tumor and 5 years later he underwent resection of the CPA mass. Twelve years after the initial diagnosis, gamma knife radiosurgery (18 Gy, 24 cm3) was needed to control a fourth ventricular recurrence followed by additional radiosurgery one year later (18 Gy, 0.6 cm3) for multiple nodules in the fourth ventricle and one cervical (C1) spinal metastasis.
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Three years later, whole spine radiotherapy was given for multiple metastases. He underwent ventriculoperitoneal shunting for hydrocephalus four years later and also received gamma knife radiosurgery because of continuous growth of the CPA lesion (14 Gy, 10.2 cm3). Later in his course, a cervical laminectomy was performed to resect three metastatic lesions to the spine. Subsequently, he was treated with temozolomide chemotherapy but there was no evidence of tumor regression. He eventually became wheelchair-bound as a consequence of the disseminated leptomeningeal disease and subsequently died. 2.1.3. Patient 3 A 27-year-old man presented with headache, nausea, and vomiting. He was found to have a tumor in the fourth ventricle, which was resected. Later on, he suffered a recurrence and required subsequent resection, radiation therapy, shunt placement, and gamma knife radiosurgery. Two years later, he was admitted because of acute renal failure. Neuroimaging studies revealed a 10 mm third ventricular/pineal lesion, and multiple fourth ventricular lesions. The patient was treated with radiosurgery (16 Gy, 1.3 cm3) but later expired from unknown causes. 2.2. Pathological findings The tumors in all three patients displayed the classical morphological features of CPPs with complex papillary structures covered by a single layer of cuboidal or low columnar epithelial cells. (Fig. 2) Histopathological examination of tissue from patient 1 revealed the typical pattern of CPP, with no signs of atypia or mitoses. Dense fibrosis with prominent hyalinization was observed in large areas of the mass. In some foci, the stroma resembled amyloid deposits, but staining with Congo red did not confirm this impression. Many of the tumor cells displayed a prominent granular cytoplasm. Occasional foci of calcification were observed. Immunohistochemical analysis was performed on tissue from Patient 1. The tumor cells were diffusely positive for transthyretin
(pre-albumin) and S100 protein. (Fig. 3) Many of the tumor cells, particularly those with a granular cytoplasm, were strongly positive for glial fibrillary acidic protein (GFAP). In many foci, GFAP positivity was observed only on the apical surface of the cells. The tumor cells were negative for cytokeratins 7 and 20 and for epithelial membrane antigen. Only a few foci contained cells positive for p53. The Ki-67 labeling index was generally low (1%). In patient 2, the proliferative indices from each of the multiple resections were compared and showed a steady increase in Ki-67 labeling index from 1.7%, to 6.0–8.5% and 9.1%, respectively. This increase in the proliferation index correlates with the clinically documented progressive increase in the aggressive behavior of the tumor.
3. Discussion CPPs are low grade tumors classified as grade I in the World Health Organization (WHO) grading scheme. They are usually treated with surgical resection alone. Dissemination of CPPs to multiple levels of the neuraxis has been observed in all age groups [13]. In the metastatic foci, the tumors usually retain distinctly low-grade histological characteristics. In most patients the pattern of spread can be traced along the CSF pathways. In this review, we analyzed cases of disseminated CPPs reported since 1961. Only adult patients, 18 years or older, were included in the review (Table 1). All patients had the diagnosis of CPP at the time of their initial presentation. Patients with the diagnoses of ACPP or CPC were excluded. In most patients, the primary lesion developed in the posterior fossa, usually in the fourth ventricle and in the CPA [14–18]. In seven patients, the tumors had already disseminated at the time of original diagnosis. Histopathologically, the metastatic lesions had the same morphological appearance (CPP, WHO grade I) as those of the primary site in 19 patients. In four patients, the secondary lesions had features of ACPP; and in two instances, the metastatic tumors were diagnosed as CPCs.
Fig. 2. Choroid plexus papilloma. (A) Intraoperative cytologic preparation, Hematoxylin and eosin (H&E) 20. (B, D) Tumor with the classical papillary architecture, H&E 100 and 400, (C) foci of dense fibrosis and hyalinization, H&E 100.
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Fig. 3. Choroid plexus papilloma. Immunohistochemical stains, (A) Transthyretin 400, (B) glial fibrillary acidic protein 400, (C) S100 protein 400, (D) p53 400.
The age of the patients ranged between 19 and 58, with a mean age of 38 years. Females represented 55.2% of the patients. The clinical presentation was variable. Over one-half of the patients, (55.2%) presented with headache, dizziness, and hydrocephalus; visual impairment was the initial presentation in 13.8% of patients. The most common site of origin was the fourth ventricle (75.9%) followed by the CPA (10.3%). Local recurrence was more frequent than metastasis to other sites (34.5%). The most common site of metastasis was to the leptomeninges (27.6%) and the suprasellar region (17.24%), respectively. The time span between initial diagnosis and the diagnosis of distant dissemination varied. It was 5 years or longer in 14 patients, while seven patients had evidence of dissemination at the time of first diagnosis. Interestingly, in the majority of the patients (65.5%) the metastatic tumors had the same WHO grade as in the primary lesion. Of all tumors, 62.1% were treated with gross total resection, 31.0% with subtotal resections, and 17.2% of patients were treated with radiation therapy after the surgical resection. In some reports, the metastatic tumors were synchronous with tumor recurrence at the primary site [19]. It is generally accepted that gross total resection is curative, and that even subtotal resections may lead to very good long-term outcomes (Safaee et al.) [20,21]. In this review, most patients had either total or subtotal resection of the primary tumor and dissemination was most often observed in patients who had macroscopically complete resections of their lesions. In most patients, the tumors that eventually became disseminated were diagnosed at age 30 years or later, and they were slightly more frequent in females than in males. It has been standard practice to treat CPPs with surgery alone and other treatment modalities (radiation therapy, chemotherapy) are given in cases of local recurrences, or metastatic disease [22,23]. It is not known whether adjuvant therapies and surgical resection can either delay, or prevent the development of metastatic CPP along the neuraxis [24,25]. Distant spread can be subdivided into three different types: diffuse leptomeningeal seeding involving drop metastasis, intraparenchymal involvement and intraventricular lesions [25–29].
Immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) analyses of non-neoplastic choroid plexus epithelial tissue show expression of both vascular endothelial growth factor receptor 2 (VEGFR2) and vascular endothelial growth factor (VEGF) ligands. This phenomenon may suggest a potential value of anti-VEGF therapy for disseminated choroid plexus tumors [11]. Other molecular pathways have also been described in the development of choroid plexus tumors including the activation platelet-derived growth factor receptor (PDGFR) and Notch 3 signaling pathways [30]. The response of choroid plexus epithelial lines expressing PDGFR-beta to imatinib, commonly used to treat chronic myelogenous leukemia, suggests the potential benefit from targeting PDGFR in CPPs with high PDGF expression [11]. Over the last decade, there has been an increasing use of molecular and immunohistochemical markers in the assessment and management of neoplasms in general. Some molecular signatures are used diagnostically to help pathologists classify tumors, whereas others are used to estimate prognosis. Most crucial, are those markers that are used to predict response to certain therapies. For example, CD117 (ckit) has been proposed as a predictive marker in CPP prognosis. We performed this stain in our case but it was non-immunoreactive. In addition, Notch 3 signaling initiates choroid plexus tumor formation. Another locus is the p53 gene. Li-Fraumeni syndrome was described as a condition associated with germline TP53 mutation that is associated with CPC. Tabori et al. showed that somatic TP53 mutation were seen in 50% of CPC, and in only 5% of CPP. Absence of TP53 dysfunction was associated with a favorable prognosis [31]. It is likely that further molecular studies may be helpful in subgrouping/characterizing patients with CPP and offer an opportunity toward improving the accuracy of risk stratification as well as the development and implementation of more effective molecularly targeted therapies. Identification of new markers might refine the current grading scheme, and provide improved insight towards predicting which tumors will be prone to disseminate or recur.
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Table 1 Disseminated choroid plexus papilloma. Reported cases in adults (18 years and older) in the literature Age Gender Symptoms
Site
Metastasis
Time to dissemination
Diagnoses initial/ metastases
Treatment of primary tumor(s)
Wilkins and Rutledge, 1961 [5] Leys et al., 1986 [19] Girardot et al., 1990 [14] Domingues et al., 1991 [13]
56 y 40 y 30 y 35 y
4th ventricle 4th ventricle Cisterna magna Foramen magnum
Cerebellum Lateral ventricle; local recurrence 4th ventricle; local recurrence Spinal leptomeninges
Gross total resection Gross total resection Surgery Subtotal resection
Cerebellopontine angle 4th ventricle
Right temporal lobe; basal cistern
5y 9y 5y Present at time of initial diagnosis Present at time of initial diagnosis 6y
CPP/NA CPP/CPP CPP/NA CPP/CPP CPP/CPP
Subtotal resection
Niikawa et al., 1993 [25]
Hydrocephalus NA NA Facial twitching and radicular leg pain 46 y Female Subconjunctival hemorrhage 38 y Male Nausea, blurred vision
CPP/CPC
Gross total resection
Shakespeare et al., 1997 [10]
27 y Female Neck pain and headache
4th ventricle
3y
CPP/CPP
Subtotal resection
Leblanc et al., 1998 [3]
19 y Female Hydrocephalus
4th ventricle
Present at time of initial diagnosis 5y 2–4 y
CPP/CPP
Gross total resection
CPP/NA CPP/ACPP
Gross total resection; radiation therapy Subtotal resection
8y 4y
CPP/CPP CPP/CPP
Gross total resection Subtotal resection; radiation therapy
5y
CPP/CPP
Gross total resection
Present at time of initial diagnosis 2.5–5 y
CPP/CPP
Subtotal resection
CPP/CPP
Gross total resection
8y
CPP/CPP
Surgery
19 y 1 month
CPP/ACPP CPP/CPP
Gross total resection Subtotal resection
Craniospinal leptomeninges; local 5y recurrence Middle cranial fossa; spinal leptomeninges 4 y
CPP/CPP
Gross total resection
CPP/ACPP
Subtotal resection
Cerebellopontine angle; cranial leptomeninges 3rd ventricle; lateral ventricle Multifocal at presentation
16 y
CPP/CPP
Gross total resection
4y Present at time of initial diagnosis
CPP/ACPP/CPC CPP/CPP
Gross total resection Gross total resection
Multifocal at presentation
Present at time of initial diagnosis
CPP/ACPP
Radiosurgery; gross total resection
Spinal leptomeninges
5 months
CPP/NA
Gross total resection
Enomoto et al., 1991 [16]
Talacchi et al., 1999 [17] Valencak et al., 2000 [28]
Male Male Female Female
Irsutti et al., 2000 [18] Jagielski et al., 2001 [22]
38 y Male Unsteady gait 33 y Female Headache, dizziness and visual impairment 48 y Female Hydrocephalus 50 y Male Hydrocephalus
McEnvoy et al., 2002 [7]
51 y Male
Hesse et al., 2002 [1]
38 y Male
Hydrocephalus
th
4 ventricle, 4th ventricle
Suprasellar region; local recurrence 3rd ventricle; spinal leptomeninges; local recurrence 4th ventricle Suprasellar region; local recurrence 3rd and 4th ventricles Temporal lobe, cerebellum, craniospinal leptomeninges; local recurrence Craniospinal leptomeninges; suprasellar 4th ventricle region Craniospinal leptomeninges 4th ventricle
McCall et al., 2006 [4]
Headache, nausea and vomiting. 22 y Female Hydrocephalus
McCall et al., 2006 [4]
30 y Female Neck pain and dizziness
4th ventricle
Yu et al., 2006 [6] Jinhu et al., 2007 [23]
Posterior fossa 4th ventricle
Ortega-Martinez et al., 2007 [26] Menon et al., 2010 [24]
30 y Male NA 32 y Female Vertigo and intermittent headache 20 y Female Progressive palsy and paresthesia in leg 43 y Male NA
Al-Abdullah et al., 2011 [15]
35 y Male
Dhillon et al., 2012 [2] Peyre et al., 2012 [27]
Headaches and blurred vision 53 y Female Headaches 46 y Female Unsteady gait, hearing loss and facial weakness
Peyre et al., 2012 [27]
39 y Female Facial numbness
Anderson et al., 2013 [11]
58 y Male
Pain in lower extremities
Spinal leptomeninges; cerebellopontine angle; suprasellar region Craniospinal leptomeninges; cerebellum; local recurrence Craniospinal leptomeninges
4th ventricle
4th ventricle Cerebellopontine angle 4th ventricle Lateral ventricle 4th ventricle; cerebellopontine angle; cavernous sinus; frontotemporal region 4th ventricle; Meckel’s cave; prepontine cistern 4th ventricle
Spinal leptomeninges; suprasellar region; local recurrence Craniospinal leptomeninges; local recurrence Spinal leptomeninges Spinal extramedullary subdural mass
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References
153
A large collaborative multi-institutional study may be needed to look at the complex molecular pathways involved in the tumorigenesis of the choroid plexus in order to produce meaningful progress in the treatment of this disease. Possible potential prognostic immunohistochemical markers such as TP53, CD117, VEGF and CD44, SV40 and polyoma viruses JC virus and BK virus, may allow the identification of the invasive potential and predict the propensity for dissemination, metastasis, and tumor behavior. Identification of such markers would help clinicians in designing better individualized treatment regimens, and may encourage the use of more aggressive treatment options during the initial course of CPP, despite its primary low-grade histological features.
Gross total resection and gamma knife radiosurgery, temozolomide Gross total resection and gamma knife radiosurgery
Gross total resection
Subtotal resection
Case Reports / Journal of Clinical Neuroscience 32 (2016) 148–154
CPP/CPP
CPP/CPP
References
4th ventricle New Case 3
New Case 2
ACPP = atypical choroid plexus papilloma, CPC = choroid plexus carcinoma, CPP = choroid plexus papilloma, NA = not available, y = years.
CPP/CPP New Case 1
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Present at time of initial diagnosis 25 y 4th ventricle
8y
17 y
Lateral, 3 and 4 ventricles; suprasellar region; cranial leptomeninges Posterior fossa masses, cerebellopontine angle, spinal leptomeninges 3rd ventricle, pineal region and 4th ventricle
th
Craniospinal leptomeninges Zachary et al., 2014 [29]
21 y Female Headache and visual changes 38 y Female Short-term memory loss and headaches 50 y Male Oscillopsia, palatal myoclonus and ataxia 27 y Male Headache, nausea and vomiting
4th ventricle; leptomeninges Lateral ventricle
rd
CPP/CPP
Conflicts of Interest/Disclosures
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[25] Niikawa S, Ito T, Murakawa T, et al. Recurrence of choroid plexus papilloma with malignant transformation. Neurol Med Chir (Tokyo) 1993;33:32–5. [26] Ortega-Martinez M, Cabezudo-Artero JM, Fernandez-Portales I, et al. Diffuse leptomeningeal seeding from benign choroid plexus papilloma. Acta Neurochir (Wien) 2007;149:1229–36 [discussion 1236–7]. [27] Peyre M, Bah A, Kalamarides M. Multifocal choroid plexus papillomas: case report. Acta Neurochir (Wien) 2012;154:295–9. [28] Valencak JB, Dietrich W, Raderer M, et al. Evidence of therapeutic efficacy of CCNU in recurrent choroid plexus papilloma. J Neurooncol 2000;49:263–8.
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http://dx.doi.org/10.1016/j.jocn.2016.04.002
Cerebellar liponeurocytoma in two siblings suggests a possible familial predisposition Stylianos Pikis a, Yakov Fellig b, Emil Margolin c,⇑ a
Department of Neurosurgery, ‘‘Korgialenio Benakio” Red Cross Hospital of Athens, Athens 11526, Greece Department of Pathology, Hadassah–Hebrew University Medical Center, Jerusalem 91120, Israel c Department of Neurosurgery, Hadassah–Hebrew University Medical Center, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel b
a r t i c l e
i n f o
Article history: Received 8 April 2016 Accepted 12 April 2016
Keywords: Biology Cerebellar liponeurocytomas Familial Inheritance
a b s t r a c t There is limited data on the genetic origin and natural history of cerebellar liponeurocytoma. To the best of our knowledge there has been only one report of a familial presentation of this rare entity. We report a 72-year-old female with a posterior fossa tumor presenting with progressive cerebellar signs and symptoms. The patient underwent total tumor resection via an uncomplicated sub-occipital craniotomy. Histopathologic examination was diagnostic for cerebellar liponeurocytoma. Her sister was previously treated for a similar tumor. Our report provides further evidence for the possible existence of a hereditary abnormality predisposing afflicted families to cerebellar liponeurocytoma development. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Cerebellar liponeurocytoma is defined by the World Health Organization (WHO) as a rare, WHO grade II, cerebellar neoplasm of adults with consistent neuronal, variable astrocytic and focal lipomatous differentiation, and with a low proliferative potential [1]. The genetic origins of this rare entity are yet to be defined and to the best of our knowledge there has been only one report on cerebellar liponeurocytoma affecting different members of the same family [2]. We report a 72-year-old woman with cerebellar liponeurocytoma whose sister was treated in our department for a similar lesion and briefly review the available literature on the molecular biology and histopathologic abnormalities associated with cerebellar liponeurocytomas.
from the right cerebellar hemisphere and compressing the brainstem and fourth ventricle. The lesion was composed of a contrast enhancing superior component and an inferior component exhibiting fat signal (Fig. 1a). Her family history was significant for a sister who underwent partial resection of a cerebellar liponeurocytoma followed by postoperative radiosurgery due to residual tumor enlargement. Six years following operation this patient was asymptomatic without any evidence of tumor recurrence. The current patient underwent sub-occipital craniotomy and gross total resection of a soft, greyish, exophytic, easily dissected tumor. Mild improvement of her symptoms was noted postoperatively and she was discharged to a rehabilitation center. At the 3-year follow-up the patient was asymptomatic without evidence of tumor recurrence on brain MRI (Fig. 1b). 3. Histopathology report
2. Case report A 72-year-old woman was admitted to our clinic due to a posterior fossa space occupying lesion diagnosed by non-contrast head CT scan obtained during head trauma evaluation following a fall. She complained of a 5-month history of progressive headache, unsteadiness, and recurrent falls. Past medical history was significant for untreated hyperthyroidism which was managed pre-operatively. On neurological examination she had ataxia, a tendency to fall on the right, and bilateral dysdiadochokinesia, dysmetria, and intention tremor, worse on the right. Brain MRI revealed a 48 43 41 mm, intra-axial, exophytic lesion arising ⇑ Corresponding author. Tel.: +972 2 677 7092; fax: +972 2 643 1740. E-mail address: [email protected] (E. Margolin).
The neoplasm of the current patient (Fig. 2I–P) displayed typical morphological features of liponeurocytoma, that is, a highly cellular neoplasm, with extensive ‘‘lipomatous” differentiation, infiltrating the cerebellar parenchyma. Occasional rosettes and areas with a prominent vascular network were evident. Most neoplastic cells were relatively uniform, with round or oval nuclei, with finely dispersed chromatin, and clear or pale cytoplasm. There was no necrosis or microvascular proliferation and the MIB-1 proliferation index was 1–3%. In contrast, the neoplasm of her sister (Fig. 2A–H) displayed atypical morphological features, with only focal, minor ‘‘lipomatous” differentiation, focal papillary/pseudopapillary appearance, focal increased mitotic activity (up to six mitotic figures/10 high-power microscopic fields) and relatively high MIB-1 proliferation index (10–15%), as well as occasional