Update: Choroid plexus carcinoma

J.Sales-Llopis
Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
Choroid plexus carcinoma (CPC) is a choroid plexus tumor originating from the ventricular choroid plexus.

They account for 2%-4% of all pediatric brain tumors, and are uncommon intracranial neoplasms accounting for 15-20% of choroid plexus tumors. About 80% of these are found in childhood. ^{1) 2)}.
Often associated with Li Fraumeni Syndrome (LFS), the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy ³⁾.

On gross pathology, choroid plexus carcinomas have a papillary or cauliflower-like appearance. They often show areas of hemorrhage and necrosis, with tumor invasion into the periventricular brain parenchyma ⁴⁾.
On histologic examination, these tumors are characterized by increased cell density, increased mitotic figures (>5 per 10 high power field), nuclear pleomorphism and necrosis.

On immunohistochemistry, choroid plexus carcinomas are almost always positive for cytokeratin, focally positive for synaptophysin, GFAP, EMA, CD 44, and CA 19-9. They are less likely to stain positive for S-100 and transthyretin. Histologically, choroid plexus carcinomas and AT/RT have overlapping features. However, the majority of choroid plexus carcinomas stain positive for INI1, whereas nuclear staining in AT/RT is almost always absent. This is a helpful distinguishing feature ⁵⁾.

TAF12, NFYC, and RAD54L co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 were identified as oncogenes that are gained in tumors in both species and required for disease initiation and progression. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair ^{6) 7)}.
Headache, diplopia, and ataxia are the most common symptoms usually caused by mechanical obstruction of cerebrospinal fluid flow followed by hydrocephalus, regardless of tumor location.

Patients present with signs and symptoms of cerebrospinal fluid obstruction, leading to increased intracranial pressure and hydrocephalus. Infants may have increased head circumference, bulging fontanelles, separate sutures, strabismus, vomiting or delayed development. Older children and adults may present with headaches, nausea, vomiting, lethargy, seizures, neurologic deficits or behavioral changes ⁸⁾.
Choroid plexus carcinomas can metastasize to the spine, therefore imaging of the entire neuraxis and CSF cytology are highly recommended. Approximately two thirds of the tumors disseminate throughout the entire CSF space. Extraneural metastases may also occur ⁹⁾.

The radiology usually shows a brilliantly enhancing heterogenous intraventricular mass invading the ependyma with edema ¹⁰⁾.
On MRI, choroid plexus carcinomas show heterogeneous intensities on both T1 and T2, with irregular enhancement and edema. Flow voids are often seen reflecting the vascular nature of the tumor. Tumor hemorrhage and necrosis are commonly seen as well ^{11) 12)}.
Choroid plexus carcinoma and papilloma was characterized by high levels of choline-containing compounds and a complete absence of creatine and the neuronal/axonal marker N-acetyl aspartate. However, the Choroid plexus carcinoma showed higher levels of choline compared with the choroid plexus papilloma, and it also had elevated lactate ¹³⁾.

Surgery is the standard first line therapy for all choroid plexus carcinomas. Gross total resection is the most important predictor of outcome ^{14)15) 16) 17) 18) 19) 20)}.
However, it is only achievable in 40-50% of cases. A number of factors contribute to the difficulty in obtaining a complete resection, including young patient age, large tumor size and vascularity. Operating on choroid plexus carcinomas carries a high risk of intraoperative hemorrhage. Pre-operative angiography, often combined with embolization, is done to help facilitate a complete resection ²¹⁾. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss.
Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue

Currently, there is no consensus on the use of adjuvant therapy, and few large-scale studies focus exclusively on the pediatric population
Multivariate Cox proportional hazard model adjusting for confounding factors showed that combined therapy was associated with better OScompared to chemotherapy alone (HR: 0.291, p = 0.027). Both chemotherapy alone and combined chemo-radiation improved OS independent of age, gender, tumor location and extent of resection, while radiation alone did not ²²⁾.

Wrede et al. conducted a meta-analysis that included 347 choroid plexus carcinomas reported in the literature prior to 2005 ²³⁾ The use of chemotherapy was associated with improved survival in all patients (P=0.0004) and among those with incompletely resected tumors (55% vs 24% at 2 years). Multivariate analysis identified the use of chemotherapy as a significant prognostic factor (P=0.001).

The role of adjuvant radiotherapy has been studied in several retrospective series ^{24) 25) 26) 27) 28) 29) 30)}.
Adjuvant radiotherapy is recommended in children and adults after a subtotal resection. Radiation is generally avoided in infants and children younger than 2-3 years.
In patients with a complete tumor resection, the role of adjuvant radiotherapy is controversial. Wolff et al. reported a cohort of 48 patients with gross total resection, half of whom received radiation. The 5 year OS was significantly higher in irradiated patients, compared with those without radiation (68% vs 14%).16 On the other hand, Fitzpatrick reported that in a cohort of 37 patients with a gross total resection, four patients did not receive adjuvant therapy, whereas the remaining 34 patients received either chemotherapy, radiation or both. The addition of chemotherapy and/or radiation after surgery did not seem to improve survival. However, the size and characteristics of the two groups (GTR with and without adjuvant therapy) were too imbalanced to draw any statistically meaningful conclusions.13 A recent SEER analysis (in abstract form) showed that radiation did not impact survival in patients with complete resection, suggesting a gross total resection may be sufficient in a subset of patients ³¹⁾.
The optimal field of radiation is also controversial. Given the high propensity for CSF seeding, some investigators have advocated for prophylactic cranial spinal irradiation without positive CSF cytology or MRI findings in the spine, whereas others use involved field radiation. A retrospective analysis of radiation fields by Mazloom et al. showed patients who received cranial spinal irradiation had improved survival compared to those who did not, 44% vs 15% at 5 years ³²⁾.
Additional studies are needed to examine the patterns of failure and need for prophylactic cranial spinal irradiation.

This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor, with few treatment options.
Five-year overall survival is about 40-50%. Gross total resection is the most consistent predictor of survival ³³⁾.

22 consecutive patients. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit.
Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2-5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy.
The administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival ³⁴⁾.

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Twenty-eight patients were documented with CPC and LFS. Eleven out of 17 patients received radiation therapy. The survival of patients receiving radiation was inferior to that of those without radiation [median (±95% confidence interval) 2-year OS=0.18 ± 0.12% versus 0.58 ± 0.12%]. The log-rank tests suggested the difference to be marginally significant (p=0.056).
This finding provides evidence for pursuing treatment approaches that do not include radiation therapy for patients with LFS ³⁵⁾.

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Twelve children with CPC (median age of 19.5 months) have been treated with HS regimens. Ten patients had >95% resection. Three patients had disseminated disease at diagnosis. Ten patients completed consolidation of whom five are alive, irradiation and disease free at 29, 43, 61, 66 and 89 months from diagnosis. Seven patients experienced tumor recurrence/progression at a median time of 13 months (range 2-43 months). Five patients received irradiation, one for residual disease and four upon progression or recurrence, of whom one is alive at 61 months. The 3- and 5-year progression-free survivals are 58% and 38% and overall survivals 83% and 62% respectively. Late deaths from disease beyond 5 years were also noted.
Head Start strategies may produce long-term remission in young children with newly diagnosed CPC with avoidance of cranial irradiation ³⁶⁾.

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Surgery associated with chemotherapy led to long-term survival in 2/3 patients. Clinical results achieved confirm that a therapeutic regimen with surgery and chemotherapy (carboplatin, cyclophosphamide, etoposide, doxorubicin, and methotrexate) is feasible and efficient as a possible adjuvant treatment ³⁷⁾.

A retrospective analysis by Wrede et al. demonstrated that in patients with an initial subtotal resection, undergoing a second resection was associated with improved survival, compared with those who did not (overall survival 69% vs 30% at 2 years). This study underscores the importance of surgery in the overall management of this disease ³⁸⁾.

A 73 years old male patient who was consulted with headache to our neurosurgery department. In cranial computed tomography, there was a mass in 4(th) ventricle and we confirmed the mass with magnetic resonance imaging. After surgery had been performed, pathology specimen was diagnosed as choroid plexus carcinoma which was rarely seen in this age group ³⁹⁾.

A 39-year-old pregnant woman whose fetus was found to have a large hydrocephalus on routine prenatal ultrasound at the 29th gestational week. A 56 mm × 73 mm mass was detected in the fetal brain arising from the brainstem and invading the third cerebral ventricle. On the subsequent fetal cranial MRI, T2-weighted image the tumor measured 55 mm × 50 mm × 48 mm and had a non-homogeneous consistency and irregular contours. Elective cesarean section was performed during gestational week 32, delivering a male fetus with a cranial circumference of 46 cm (normal circumference, 30 cm) and a birth weight of 2920 g. The infant expired 4h following delivery. Autopsy revealed a carcinoma of the choroid plexus. The case, like others, suggests that MRI is more accurate than prenatal ultrasound in prenatal brain tumor diagnosis. More precise morphological detail is provided by MRI, which improves surgical planning and survival ⁴⁰⁾.

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A 1-year-old male child presented with ataxia and intracranial hypertension since 2 months. The noncontrast computerized tomography (CT) scan showed a heterogenously hyperdense lesion in right posterior fossa region with gross hydrocephalus. The magnetic resonance imaging (MRI) revealed a posterior fossa lesion with the epicenter being located in the 4th ventricle, the presence of a solid and cystic component with extension into the right cerebellar hemisphere. The cystic component was uniformly hyperintense on MRIT1 and T2 sequences, and the fluid attenuation inversion recovery (FLAIR) sequence. The solid component appeared isointense on T1, T2 sequences and had a heterogeneous contrast enhancement . Although diffusion weighted imaging (DWI) would provide us with added information, this was not available as the patient was referred to us with imaging. At surgery, the cyst had machine oil like fluid, usually characteristic of craniopharyngioma cysts. The solid component of the tumor was soft, friable, and vascular with a clear margin separating the tumor from the brain stem with an absent interface and vermian infiltration at places. ⁴¹⁾.

A rare extraventricular, intraparenchymal choroid plexus carcinoma (CPC). This 6-year-old girl presented to the emergency department with a 1-week history of headaches, nausea, and vomiting. Imaging studies revealed an intraaxial cystic and solid mass located in the right frontal lobe with central nodular enhancement and minimally enhancing cyst walls. Gross-total resection was accomplished via craniotomy without complications. The initial pathological diagnosis was atypical teratoid/rhabdoid tumor (AT/RT); however, immunostaining for INI1 protein (using the BAF47/SNF5 antibody) showed retention of nuclear staining in the tumor cells, resulting in a change in the diagnosis to CPC. There was no evidence of recurrence at the last follow-up 2.5 years after treatment, which supports the diagnosis of CPC over AT/RT. This case emphasizes the importance of immunostaining for INI1 protein for distinguishing CPC from AT/RT in cases with atypical or indeterminate features ⁴²⁾.