Acta Neurochir DOI 10.1007/s00701-014-2138-1

CLINICAL ARTICLE - BRAIN TUMORS

Clinical outcome of adult choroid plexus tumors: retrospective analysis of a single institute Erhan Turkoglu & Hayri Kertmen & Ahmet Metin Sanli & Evrim Onder & Ahmet Gunaydin & Levent Gurses & Behzat R. Ergun & Zeki Sekerci

Received: 4 March 2014 / Accepted: 16 May 2014 # Springer-Verlag Wien 2014

Abstract Background Choroid plexus tumors are rare brain tumors with clinical features that vary according to the histological grade. We reviewed the treatment outcomes of 15 adult patients with choroid plexus tumors, focusing on surgical outcomes and current therapeutic strategies. Method Patient demographic and clinical characteristics, operative findings, adjuvant therapies, disease progression and survival rates were reviewed. Results The median age at diagnosis was 33.7±10 years (19– 59 years) for patients with choroid plexus tumors. Postoperative chemotherapy was given to 26.7 % of patients, and 13.3 % of patients received radiotherapy. The Ki-67 labeling index and mitotic index increased at higher histological grades. All of the choroid plexus papilloma and atypical choroid plexus papilloma patients have survived. The overall survival rate of patients with choroid plexus carcinoma was 50 % in the first year, but none of the patients survived to the second year. Five patients underwent permanent cerebrospinal fluid diversion surgery because of hydrocephalus or subdural effusion. Conclusions Choroid plexus papilloma and atypical choroid plexus papilloma patients can be treated with complete surgical resection. Choroid plexus carcinoma has a poor prognosis, E. Turkoglu : H. Kertmen : A. M. Sanli : A. Gunaydin : L. Gurses : B. R. Ergun : Z. Sekerci Neurosurgery Clinic, Ministry of Health, Diskapi Yildirim Beyazit Research and Educational Hospital, 06610 Ankara, Turkey E. Onder Pathology Clinic, Ministry of Health, Diskapi Yildirim Beyazit Research and Educational Hospital, 06610 Ankara, Turkey E. Turkoglu (*) Cukurambar Mah. Ogretmenler Cad. Kardelen Apt. No:5/6, 06290 Ankara, Turkey e-mail: [email protected]

and aggressive multi-modal treatments are generally needed for treatment. Chemotherapy and radiotherapy are important adjuvant therapies for choroid plexus carcinoma. If hydrocephalus and/or subdural effusion occur, permanent cerebrospinal fluid (CSF) diversion should be added to the therapeutic strategy. Keywords Atypical choroid plexus papilloma . Choroid plexus carcinoma . Choroid plexus papilloma . Choroid plexus tumors . Hydrocephalus . Outcome . Surgery . Therapy

Introduction Choroid plexus tumors (CPT) are rare, mostly benign, slowgrowing, primary brain tumors arising from the choroid plexus epithelium. The choroid plexus is near the ependyma, and tumors of the choroid plexus follow the ventricle or invade the brain parenchyma that is adjacent to the ependyma [24]. The average annual incidence in the non-pediatric population is approximately 0.3 persons/1 million population/1 year [16, 25, 28]. These tumors account for less than 1 % of brain tumors in all age groups but are seen more frequently in children, especially in the first 2 years of life, with an incidence of 1.5–4 % in this age group [8, 29]. While the most common site in children is supratentorial (the atrium of the lateral ventricles), these tumors are predominantly located in the fourth ventricle and the cerebellopontine angle in adults [20]. Supratentorial lesions occur at a median age of 1.5 years, whereas infratentorial tumors present at a median age of 22 years [19]. Choroid plexus tumors commonly cause signs and symptoms of obstructive hydrocephalus, due to their location. The preference of surgical approach and the treatment of hydrocephalus are very challenging. High vascularization, adherence to lower cranial nerves in posterior fossa and deep intraventricular location hinder surgery [4].

Acta Neurochir

Choroid plexus papilloma (CPP) is benign, and total surgical removal is curative. Recurrences are infrequent and the prognosis is good [7, 22]. Some CPPs behave atypically and have an increased mitotic count; such tumors have been classified as a new entity, known as atypical choroid plexus papilloma (ACPP) [13]. Choroid plexus carcinoma (CPC) has infiltrative and anaplastic features such as a high recurrence rate, rapid progression and leptomeningeal seeding. Eighty percent of CPCs arise in children [4]. This malignant tumor has a dismal prognosis, and curative therapy is not currently available. Various adjuvant therapies have been used after surgical removal of the tumor, and there have been encouraging results from a number of reports of attempted multimodal adjuvant treatment [3, 34]. The event-free-survival rate was 92 % in CPP, 83 % in ACPP and 28 % in CPC. Metastases from CPTs are quite rare, but can occur in patients with CPC and CPP [2, 10, 14, 32]. In the literature, the most reports concentrate on pediatric patients. In the present study, we retrospectively analyzed the clinical data of the adult patients who were treated at our institute. We detail our experience about the best management approaches, and assess the surgical outcomes among patients with CPTs.

Fig. 1 Atypical choroid plexus papilloma with scattered mitoses and some degree of nuclear pleomorphism (HE X 400)

increased cellular density, nuclear pleomorphism, blurring of the papillary pattern and necrosis [18]. Table 1 shows the clinical and pathologic characteristics of patients in this study. Current functional status and neurological condition were evaluated using the Karnofsky Performance Scale (KPS). Tumor recurrence or progression was defined as a new or progressive on follow-up MRI. There was no neuraxial metastatic spread in any of the patients. Patients who were younger than 18 years old were excluded from the study.

Materials and methods

Surgical and adjuvant treatment

Clinical and pathologic characteristics of the patients

Surgical resection was performed based on preoperative neurological and radiological examinations in all patients. All surgeries were performed using classical standard approaches. Tumors located in the fourth ventricle were operated using suboccipital median craniotomy with opening of the foramen magnum. The surgeons preferred splitting of the inferior vermis or a telovelar approach, depending on the precise location of the tumors. A subtemporal transcortical approach was used for tumors in the trigon and a supracerebellar infratentorial approach was used for tumors in the posterior part of the third ventricle. The neurosurgeon preferred the ideal surgical approach for tumors located in the lateral ventricles. Gross total resection (GTR) was achieved in nine of the nine patients with CPP and in two of the four patients with ACPP. Two patients with CPC underwent subtotal resection (STR) because of massive bleeding. They received radiotherapy (at doses of 50 to 55 Gy) and chemotherapy as adjuvant therapy for residual tumors, as well as gamma knife radiosurgery for recurrent tumors. No patient with CPP received adjuvant treatment. Two patients with ACPP received radiotherapy as the initial adjuvant treatment 3 weeks after surgery. Two patients with CPC received chemotherapy (melphalanetoposide-carboplatin) after radiotherapy. Tumor recurrence was defined as the appearance of residual tumor growth or the development of new lesions on magnetic resonance (MR) images. All instances of tumor recurrence occurred in the CPC patients.

We analyzed adult patients who underwent surgery for CPTs between January 2002 and December 2012 at the Neurosurgery Clinic, Ministry of Health, Diskapi Yildirim Beyazit Education and Research Hospital. A total of 15 surgically treated adult patients with pathologically confirmed CPT were reviewed retrospectively in this study. Clinical, histopathological and operative reports, as well as outpatient records were reviewed. All surgical procedures were performed by the senior authors (AMS, BRE, and ZS), and the hematoxylin eosin (HE) and Ki-67 (clone MIB-1; Optistain) stained preparations were re-evaluated by a pathologist experienced in neuropathology (EO). The pathological evaluation was done according to the criteria of World health Organization (WHO) 2007 classification [17]. Increased mitotic activity, increased cellularity, nuclear pleomorphism, blurring of papillary pattern and presence of necrosis are accepted as the findings of atypia (Fig. 1). CPP is composed of fibrovascular connective tissue fronds covered by a single layer of uniform cuboidal to columnar epithelial cells with round or oval nuclei. The mitotic activity of CPP is very low. ACPP is defined as CPP with increased mitotic activity, and a mitotic index of two or more mitoses per ten high-power fields (HPF) is sufficient for the diagnosis of ACPP. CPC has signs of malignancy. At least four of five features should be present: mitoses greater than five per ten HPF,

Acta Neurochir Table 1 Clinical and tumor characteristics of 15 patients with choroid plexus tumors Clinical factors Sex Age Presentation KPS NE Tumor location Extent of removal Tumor subtype Radiotherapy Chemotherapy

Male/female 33.7±10 (19–59 y.o.) HA/Nausea/Vomiting/Hydrocephaly/Ataxia/Others Pre-op/Post-op Normal/Papilledema/Nystagmus/Others 3rd ventricle/4th ventricle/Lateral ventricle Total/subtotal CPP/ACPP/CPC ACPP CPC

Number of patients

%

6/9

40/60

13/8/8/4/3/5 80/90 7/5/2/5 2/9/4 11/4 9/4/2 4 2

87/53/53/27/20/33 47/33/13/33 13/60/27 73/27 60/27/13 27 13

ACPP: Atypical choroid plexus papilloma, CPC: Choroid plexus carcinoma, CPP: Choroid plexus papilloma, HA: Headache, KPS: Karnofsky performance scale, NE: Neurological examination, y.o.: years-old

All of the patients received perioperative external ventricular drainage (EVD). EVD catheters were removed after hydrocephalus or intraventricular hemorrhage had resolved. Five of the patients who presented with hydrocephalus initially required permanent cerebrospinal fluid (CSF) diversion with a ventriculoperitoneal shunt (VPS). Two patients with VPS experienced subdural fluid collection and underwent burr hole trephination and subdural drainage. Statistical analysis Data analysis was performed using SPSS for Windows, version 11.5 (SPSS Inc., Chicago, IL, United States). Metric discrete variables are reported as mean ± SD or median (min-max) where applicable; otherwise, the number of cases and percentages are used to present categorical data. The Kruskal–Wallis test was used to evaluate whether the median differences in Ki-67 and mitotic index among diagnostic groups were statistically significant. A p value of less than 0.05 was considered statistically significant. When the p values derived from the Kruskal–Wallis test statistics were statistically significant, the Bonferroni-adjusted Mann Whitney U test was used to determine differences among the groups. According to the Bonferroni correction, p values < 0.017 were considered statistically significant. Kaplan–Meier survival analysis was also used to determine both 3–5 and 10year overall survival (OS) rates and mean survival times with 95 % confidence intervals.

Results The median follow-up for all the patients was 5 years (range, 2–10 years). The male to female ratio was 6:9. The median

patient age was 33.7±10 years (range, 19–59 years). The initial symptoms included headache in 13 patients (86.7 %), nausea in eight patients (53.3 %), vomiting in eight patients (53.3 %), hydrocephalus in ten patients (67 %) and other neurological symptoms, such as ataxia, in eight patients (53.3 %). The tumors were located in the third ventricle in two patients (13.3 %), the fourth ventricle in nine patients (60 %) and the lateral ventricle in four patients (26.7 %). The mean preoperative and postoperative KPS scores were 80 (range, 20–100) and 90 (range, 20–100), respectively. The KPS improved by > 20 points in three patients early after surgery, and in 7/15 patients during further follow-up. We observed permanent postoperative worsening (KPS>20) in one case with tumor located in the fourth ventricle, but the patient improved with time. A total of 3/15 patients never improved (KPS 2 mitoses/10 HPF) was the only independent factor affecting recurrence [25]. ACPP is a newly defined entity in which the Ki-67 labeling index and the mitotic count for are between those for CPP and CPC. In our study, the mean value of Ki-67 was 0.4±0.51 % in CPP, 12.3±7.76 % in ACPP, and 37.1±14.32 % in CPC. The mean mitotic count was 0.2±0.48 per ten HPF in CPP, 7.4±5.33 per ten HPF in ACPP, and 23.8±6.17 per ten HPF in CPC. The Ki-67 index values were intermediate in both the ACPP and CPC groups, and the mitotic index value was high in the CPC group, which is consistent with prior publications [15, 23]. Considering the difference between those two histotypes in terms of survival rates, it could be suggested not to take Ki-67 into account for the differential diagnosis. CPTs in adults may have a different etiology than their pediatric counterparts [4, 33]. These tumors predominantly arise in the atrium of the lateral ventricle in children and in the

Table 3 Ki-67 labeling and mitotic index in CPTs

Fig. 3 Comparison of mitotic index among diagnostic groups. The horizontal lines in the middle of each box indicate the median, while the top and bottom borders of the box mark the 25th and 75th percentiles, respectively. The whiskers above and below the box mark the maximum and minimum mitotic index. Asterisks represent extreme cases.

Pathology

n

Ki-67

Mitotic Index

ACPP + CPCa CPP p value a

6 9

7.5 (5–10) 2 (1–8) 0.005

3.5 (2–4) 0 (0–1) < 0.001

a

Mann–Whitney U

Acta Neurochir Fig. 4 a axial b coronal and c sagittal T1-weighted cranial MRI with contrast of a 19-year-old woman who presented with headache and nausea demonstrated a highly vascularized well-defined tumor located in the right lateral ventricle. The histological diagnosis was atypical choroid plexus papilloma, WHO grade II. Postoperative fifth year control T1-weighted axial (c), coronal (d) and sagittal (e) cranial MRI with contrast showed total tumor excision and no recurrence

fourth ventricle in adults [20]. The majority of the tumors were in the fourth ventricle (9; 60 %), and the remainder were in the lateral (4; 26.7 %) and the third ventricles (2; 13.3 %), and for the mostly benign histologies (CPP, 9/15, % 60). Boström et al. reported on 14 adult patients, 86 % of them with a CPP and 14 % of them with ACPP, and most of them located in the posterior fossa. Similarly, these findings are well documented in the literature [4, 26, 27, 30, 31]. Our findings were consistent with these previous studies. The clinical course and presentation are related to hydrocephalus and associated symptoms of increased intracranial pressure. While children have a slower onset of symptoms, with headaches and visual symptoms as the major presenting symptoms, adults have a more rapid clinical presentation due to fourth ventricular obstruction. Our findings were similar to general observations in the existing literature [11, 21]. 1,0

,8

,6

Overall Survival

,4

,2

0,0 0

2

4

6

8

10

12

Follow-up time (years)

Fig. 5 Kaplan–Meier cumalative overall survival curve for all patients

The primary treatment for CPTs is surgical resection. Extensive resection is associated with prolonged survival [22, 23]. Sampath et al. reported that gross total excision is more feasible in adults with better outcomes. In their series, the benign character of the tumors in adult patients (95 % CPP) certainly affected outcomes of the patients [27]. Boström et al. confirmed that survival after CPT surgery in adults is usually good, but they also stated that functional outcomes were not satisfactory (21 % of the patients, KPS

Clinical outcome of adult choroid plexus tumors: retrospective analysis of a single institute.

Choroid plexus tumors are rare brain tumors with clinical features that vary according to the histological grade. We reviewed the treatment outcomes o...
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