Childs Nerv Syst (2015) 31:1751–1772 DOI 10.1007/s00381-015-2783-6

SPECIAL ANNUAL ISSUE

Posterior fossa tumors in infants and neonates Pietro Spennato 1 & Giancarlo Nicosia 1 & Lucia Quaglietta 2 & Vittoria Donofrio 3 & Giuseppe Mirone 1 & Giuliana Di Martino 1 & Elia Guadagno 5 & Maria Laura del Basso de Caro 5 & Daniele Cascone 4 & Giuseppe Cinalli 1

Received: 30 May 2015 / Accepted: 2 June 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Introduction Management of posterior fossa tumors in infants and neonates is challenging. The characteristics of the young babies make surgery very difficult, sometimes precluding a safe complete removal. Methods A review of the literature was undertaken to examine the incidence, histology, surgical aspects, and prognosis of posterior fossa tumors in the first year of life. Therapeutical strategies of the most frequent tumor types are also discussed in detail. Results Histology is dominated by tumors with aggressive behavior, such as medulloblastomas, atypical teratoid/ rhabdoid tumors, and anaplastic ependymomas. The most important surgical considerations in small children are the small circulating blood volume; the poor thermoregulation; and incomplete maturation of the brain, of the skull, and of the soft tissue. Treatment toxicity is inversely related to the age of the This work is dedicated to the memory of Roberta Migliorati, M.D. (1955–2014), who dedicated her whole life to the care of children affected by brain tumors. * Giuseppe Cinalli [email protected] 1

Division of Neurosurgery, Santobono-Pausilipon Children’s Hospital, Naples, Italy

2

Division of Oncology, Santobono-Pausilipon Children’s Hospital, Naples, Italy

3

Division of Pathology, Santobono-Pausilipon Children’s Hospital, Naples, Italy

4

Division of Neuroradiology, Santobono-Pausilipon Children’s Hospital, Naples, Italy

5

Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy

patients. Radiation therapy is usually considered as contraindicated in young children, with few exceptions. Proton therapy is a promising tool, but access to this kind of treatment is still limited. The therapeutic limitations of irradiation render resection of this tumor and adjuvant chemotherapy often the only therapeutic strategy in many cases. Conclusions The overall prognosis remains dismal because of the prevalent aggressive histologies, the surgical challenges, and the limitations of adjuvant treatment. Nevertheless, the impressive improvements in anesthesiology and surgical techniques allow, in the vast majority of the cases, complete removal of the lesions with minor sequelae in high-volume referral pediatric centers. Keywords Medulloblastoma . Atypical teratoid rhabdoid tumor . Ependymoma . Pilocytic astrocytoma . Pilomyxoid astrocytoma . Infants . Neonates . Posterior fossa tumors

Introduction The survival of infants and neonates with brain tumors is significantly worse than that of older children, both overall and within specific tumor types. They are very difficult to manage, for several reasons that markedly increase morbidity and mortality [22]. Clinical presentation is often subtle (macrocrania, irritability, poor feeding, failure to thrive), so that the tumor can reach great size before being diagnosed. The circulating blood volume of the young baby is smaller, but the head is relatively large, thermoregulation is poor and maturity of the brain, of the skull, and of the soft tissue of the head is incomplete [39]. Babies with posterior fossa tumors are at even higher risk than babies with tumors in other locations, because of the increased risk of hypotension and hypoxia, (both during the diagnostic work up and during all

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phases of surgery, including prone positioning), the possible compromise of lower cranial nerves, with impaired feeding and airway protection, and the higher incidence of highgrade tumors. Surgery is also difficult in this age group. Safe sitting position can be very difficult in infants and neonates. In the prone position, bleeding is more important even from the dura due to the persistence of fetal dural venous pattern in infants, and tumors with high-grade histology can be highly vascularized. Fortunately, posterior fossa tumors in young babies are very rare, with supratentorial tumors predominating. Treatment toxicity is inversely related to the age of the patients. Radiation therapy has very significant limitations in younger children, with few exceptions. The therapeutic limitations of chemotherapy and irradiation render resection of posterior fossa tumors in this age group a therapeutic and prognostic tool of utmost importance. Maximal cytoreductive surgery is the goal with many infantile brain tumors because it significantly correlates with improved outcomes [22]. Prior to the mid-1980s, the treatment for infants and very young children with brain tumors was surgery followed by radiation (with a 10–20 % dose reduction according to age). The results were poor, in terms of survival and significant neurotoxicity. Therapeutic approaches changed, and, in particular, prolonged postoperative chemotherapy was used with delayed irradiation in babies with malignant tumors who were <3 years of age at diagnosis.

Terminology According to Boldrey et al., a tumor is classified as Bcongenital^ if symptoms are detected at birth or in the first few days of life; as Bneonatal^ if symptoms are recognized in the first 2 months of life; as Binfantile^ if symptoms are recognized in the first 12 months of life [4]. However, this distinction is not well demarcated, so many series differentiate children with tumors at birth (Bcongenital/neonatal tumors^), and children under the age of one or two (Binfantile tumors^) [39].

Epidemiology The estimated incidence of brain tumors in children is 2–3.5 per 100,000. The incidence of intracranial tumors in children less than 1 year of life is variable in the literature and ranges between 1 and 10 % of all childhood intracranial tumors, with half of those arising in the first 6 months of life. They have an overall annual incidence of 31.2 cases per million in children less than 1 year of age [3]. Congenital brain tumors are uncommon. They account for less than 5 % of all cancers diagnosed in newborn and stillborn children, with a frequency of 1.1 per 100,000 births [17, 18]. They comprise 18 % of brain

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tumors presenting during the first year of life and only about 0.5–1.5 % of those in childhood. Teratoma is the most common congenital brain tumor, comprising more than one third of all cases. Very young babies differ from older children, because the infratentorial compartment is not the commonest site of primary intracranial tumors. As reported by Souweidane, a summary of several large published series, with more than 1000 cases, indicates that in children younger than 2 years of age, infratentorial tumors account for 32.4 %. In children less than 2 months of age, the distribution of posterior fossa tumor falls to 17.9 % [39]. If analysis of location is restricted to malignant tumors, however, these proportions change, that is, the posterior fossa is the site of medulloblastoma (the most common malignant brain tumor in this age group) and the location of most ependymomas in the very young [8]. Histology is very variable, with predominance for highgrade and aggressive tumors, with great metastatic potential. Medulloblastoma is the most common brain tumor in infants, accounting for nearly 50 % of newly diagnosed brain tumors in children <2 years of age. Often, brain tumors diagnosed in the first year of age belong to the categories of embryonal tumors: mixed neuronal-glial tumors, and more rarely ependymal tumors and choroid plexus tumors.

Etiology Epidemiological studies have rarely identified etiologic factors related to brain tumors in children. In several congenital syndromes, a genetic predisposition to brain tumor has been established. The most frequent syndromes associated with brain tumors at young age are Li-Fraumeni syndrome (malignant astrocytomas and choroid plexus tumors), rhabdoid predisposition syndrome (atypical teratoid rhabdoid tumor), Turcot and Gorlin syndrome (medulloblastoma), Aicardi syndrome (medulloblastoma and choroid plexus papillomas), Rubinstein-Taybi (medulloblastoma, meningiomas, and oligodendrogliomas), and neurofibromatosis (gliomas). They are usually transmitted as autosomal dominant traits, with most alleles acting as tumor suppressor genes (p53 for LiFraumeni syndrome, INI1 protein for rhabdoid predisposition syndrome). It is possible that genetic predisposition is underestimated. Screening for these syndromes, in siblings and other relatives of young children with brain tumors, should be recommended [39]. Ionizing radiation is established as a cause of primary brain tumors. The risk is dose and age dependent, with younger children being more susceptible. The main source of exposure is diagnostic and therapeutic radiation, environmental, and military accidents. The implication of parental exposure to cured meats, polycyclic aromatic hydrocarbons (smoking or occupational exposure) is controversial [28]. Maternal

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exposure to viral infections during gestation has been reported to increase the odds of a brain tumor during childhood [11]. No unequivocal predictive value has been found for exposure to pesticides, petrochemical products, exhaust fumes, and other environmental agents [39, 45].

Clinical presentation Clinical presentation varies according to the location of the tumor, its rate of growth, its aggressiveness, and to the age of the child. It can vary from isolated frequent vomiting which can be misdiagnosed as a gastrointestinal disorder, to even sudden neuropsychological changes. So diagnosis is often missed in the early presentation, and a child may go through several investigations before the tumor is discovered. Localizing neurological signs are rare, and subtle constitutional signs of failure to thrive, vomiting, and behavioral changes predominate. The most consistent clinical finding for posterior fossa tumors is signs and symptoms related to increased intracranial pressure caused by the obstruction of the cerebrospinal fluid pathways. The signs are even more subtle in infants who can present only with irritability, poor feeding, failure to thrive, and lethargy. Macrocephaly, bulging fontanels and diastasis of the cranial sutures are signs of hydrocephalus. Other symptoms and signs of increased intracranial pressure are decreased level of consciousness, irritability, poor feeding, failure to thrive, inappropriate sleepiness, and limited up-gaze or forced down-gaze (i.e., sun-setting sign). Papilledema is rare in infants. Intermittent vomiting, macrocephaly, and inability to elevate the eyes are the most frequent symptoms of a posterior fossa tumor in the infant. Facial and lower cranial nerve palsies have a specific importance which can help to localize the tumor mass, usually at the level of the cerebellopontine angle. In the absence of hydrocephalus, in tumors involving the brain stem and in very young babies, the clinical picture is dominated by hypotonia (floppy infant) and failure to achieve neurodevelopmental milestones. In neonates, respiratory distress can also be a presenting symptom. Extremely acute presentation is possible. In our experience, the histological type more frequently associated with acute presentation was the ependymoma. Acute presentation can be related to intratumoral hemorrhage inducing acute hydrocephalus (Fig. 1a, b) or with a seizure inducing sudden decompensation of a long-standing situation. This can be heralded by generalized tonico-clonic seizures (Fig. 2) or by cerebellar fits with opisthotonic posture caused by cerebellar tonsils or tumor herniation through the foramen magnum. In both cases, emergency procedures must be performed. External ventricular drainage (EVD) must be placed

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emergently as soon as the diagnosis is obtained, but the posterior fossa tumor should be approached immediately thereafter, because the CSF withdrawal from the supratentorial ventricular system carries the risk of worsening the tumor hemorrhage, upward herniation of posterior fossa structures with further brainstem compression and death. The variety of symptoms at presentation highlights the need to investigate any child with abnormal symptoms, especially related to possible intracranial pathology. Cerebral ultrasound and magnetic resonance imaging are the diagnostic modality of choice in this age group, when hydrocephalus and brain mass is suspected. In case of brain tumor, brain and spinal cord MRI, looking for possible tumor spread, should be performed. In case of associated fever or previous episodes of meningitis, careful examination of the occipito-cervical skin in the midline should be performed, in order to rule out a dermal sinus that can be associated with very large dermoid tumors in the posterior fossa.

Treatment Management of hydrocephalus Hydrocephalus is the common presenting feature of young children with posterior fossa tumors. Most of these children are affected by high-grade tumors involving the fourth ventricle (medulloblastomas, atypical teratoid/rhabdoid tumor (AT/ RT), ependymomas). In a high percentage of cases, hydrocephalus will persist despite complete tumor removal [5]. A newborn or infant should not be operated on the posterior fossa if hydrocephalus has not been treated either before the posterior fossa surgery or during the posterior fossa surgery but before dural opening, by any mean the surgeon prefers. The reason for this is that normalization of intracranial pressure carries significant advantages for the surgeon, facilitating dural opening by decreasing the cerebellar swelling and decreasing the venous pressure, thus decreasing the blood loss during dural opening and during tumor dissection and debulking. Opening the dura in a newborn without previous normalization of intracranial pressure could result in immediate severe cerebellar swelling through the initial dural opening. This could result in significant cerebellar damage and more difficult control of brisk hemorrhage from the median occipital dural sinus that could be complicated by sudden drop in arterial pressure. The ideal management of hydrocephalus is still a matter of debate. The choice between the available options is very wide and is usually left to the surgeon’s preference. It should be kept in mind that any CSF diversion procedure carries the risk of infratentorial complications like upward tumor herniation or intratumoral hemorrhage [10]. Therefore, during any CSF diversion procedure, care should be taken to avoid excessive

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Fig. 1 Seven-month-old baby boy with a 10-day history of vomiting in the morning. The day of admission the parents found him at bed with no gaze pursuit and severe neck stiffness. When admitted in the emergency room the patient was unconscious in opisthotonus. CT scan revealed a hemorrhagic tumor in the fourth ventricle (a) with long standing hydrocephalus (b). After emergency EVD, the tumor was removed completely and was proven to be anaplastic ependymoma

CSF loss during surgery. Steroids and early surgery are usually preferred if hydrocephalus is not present. External ventricular drainage (EVD) can be placed at admission if clinical

conditions require an emergency procedure. Otherwise, a frontal EVD can be placed in a standard fashion in the OR immediately before positioning the patient in the prone or

Fig. 2 Nineteen-month-old baby girl with long-standing history of sporadic vomiting. The day of admission she presented with acute headache with loss of consciousness followed by generalized seizure. She was admitted to the emergency room in cardiopulmonary arrest and bilateral mydriasis. After immediate resuscitation, an EVD was placed in

emergency and tumor was removed but mydriasis never resolved, the child never recovered and eventually died 2 days after surgery. Histology revealed grade II ependymoma. Note the calcifications on the CT scan

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sitting position for posterior fossa surgery. As an alternative, an EVD can be implanted through an occipital burr hole in the same surgical field of the posterior fossa opening, but electromagnetic navigation guidance of the ventricular catheter is advised if this option is to be preferred. In either case, care should be taken not to lose too much CSF during EVD placement and leave it closed until immediately before dural opening. Placement of a ventriculo-peritoneal (VP shunt) can be considered in very small babies with metastatic or multicentric tumor at presentation, or in cases with unusually big lesions that are not candidates for upfront radical excision. These patients in fact, in this age group, carry a very high risk of persisting postoperative hydrocephalus, and EVD management in the postoperative period can be associated with complications or events that can delay the beginning of adjuvant treatment resulting in significant compromise of timely adjuvant treatment. Endoscopic third ventriculostomy (ETV) is a very valid option for preoperative management of hydrocephalus in older children (>2 years of age), but in our experience, in very young babies (under 6 months of age) harboring tumors with radiological features of malignancy, the results of ETV was disappointing. In fact, almost all children required ventriculoperitoneal (VP) shunt in the postoperative period in spite of complete tumor resection [35]. If there is metastatic tumor at presentation, an endoscopic approach may be instead very useful to biopsy an intraventricular lesion. The patient can then be referred to oncologists before posterior fossa surgery [13]. Our current policy in case of very young children with acute hydrocephalus and tumor with radiological features of malignancy is to offer VP shunt urgently in case of metastatic or multicentric disease, associated with endoscopic biopsy of intraventricular lesions if present. Another option is to offer ETV associated with implant of Ommaya reservoir: especially in case of strong suspicion of AT/RT, the reservoir can be used for urgent withdrawal of CSF, and to administer intrathecal chemotherapy in the post-op period, if included in the treatment protocol. In this age group, we rarely prefer the implantion of an external ventricular drainage immediately before surgery, because of the risks related to the presence of an EVD in the ICU in the immediate post-operative period. Preparation and positioning With few exceptions, the extent of surgical resection is positively related to outcome. However, surgical resection poses additional problems, compared with older children. This is evidenced by a higher mortality rate in the literature in children below 2 years of age. The mortality rates ranges from 7.3 to 33 % also in recent series [39]. Therefore, younger children should be managed by an experienced team, with the

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adjunct of all the more modern advancements in neuroanesthesia, pediatric intensive care unit monitoring, preoperative imaging, and microsurgical technique. Another important issue is the risk of hypothermia in infants. Some simple maneuvers can help to minimize such risk [39]. The ambient room temperature should be elevated. Before surgical scrubbing, the preparatory solutions can be heated in the surgical incubator before use. The child can be warmed using warm air currents or convective warming blankets. Intravenous fluids should be warmed during administration. Most deaths can be attributed to blood loss. Peripheral intravenous access that can accommodate rapid transfusion is essential, as is continuous blood pressure monitoring with an arterial line. Appropriately crossmatched whole blood should be available in the surgical suite at the initiation of the procedure. In case of blood loss equivalent to one circulating blood volume, supplementing platelets and plasma should be considered. The circulating blood volume of most infants is estimated at 80 ml/kg. Three main surgical positions can be used to approach posterior fossa tumors in infants: the prone, the sitting, and the lateral position. The choice of the patient’s position is based on the tumor location and on the surgeon’s preference and experience. The prone position (Fig. 3a) is the most widely utilized and the most comfortable for the surgeon. It provides a wide access to the cerebellar hemisphere, the IV ventricle, and the cervico-medullary junction. Occasionally, especially in the prone position, flexion of the neck may occlude the endotracheal tube, which will result in high inflating airway pressures and venous bleeding in the operative field. This requires immediate readjustment of the head holder. The surgeon must communicate with anesthesiologist that the head will be well flexed. If not, when head is flexed, the ET tube may go in too far and be endobronchial. The sitting position gives a more direct access to the inferior aspect of the tentorium and the upper cerebellar vermis. This position also offers the advantage of a blood-less operating field, but with an increased risk of air embolism and systemic blood hypotension. This position can be used at any age [31]. The lateral or park bench position may be indicated for tumors, such as AT/RT and ependymomas, with prevalent extension in the cerebellopontine angle. In our experience, the prone position is utilized in almost all procedures, with a midline skin incision. However, for laterally extending tumors, such as cerebellopontine (CP) angle ependymomas, a far lateral suboccipital craniotomy with wide lateral exposure is necessary. To obtain this, asymmetric dissection of the neck muscles is necessary in order to have the easiest possible line of sight of the main tumor axis. This is usually obtained in adults and in younger children with a Hockey stick incision, but in small babies, this incision has been definitively abandoned in our practice because an area of necrosis usually develops in the upper part of the skin flap. Instead, a

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The thinness of the infant skull and the presence of cranial sutures create a potentially dangerous situation for using rigid pin fixation. There is no general consensus on the safe use of pin fixation in young children, but a common recommendation is to avoid pin fixation in children younger than 2 years of age. Non-rigid fixation such as a cushioned horseshoe head frame is usually used (Fig. 3b). For prolonged procedures, pressure necrosis of the scalp may be a concern. This can be avoided by intermittent intraoperative repositioning. Surgical treatment

Fig. 3 a Five-month-old infant in prone position with the head in a horseshoe head rest. All the pressure points are well padded. The patient underwent neurophysiologic monitoring (same case of Fig. 4). b Three-month-old baby with the head fixed in a non-rigid fixation system. The pins are replaced by gelatin pillows (Doro, ProMedInstruments GmbH, Freiburg, Germany)

retromastoid BS^-shaped skin incision is systematically used, allowing midline dissection at the muscles level through the avascular ligamentum nuchae, and at the same time allows very wide lateral exposure and excellent line of sight through the main tumor axis because muscle retraction is much more effective than when using a pure midline incision (Fig. 4a–c).

As a rule, no attempt to posterior fossa surgery should be performed without previous treatment/control of hydrocephalus by any mean the surgeon prefers (EVD, ETV, VP shunt). Tumor histology influences not only long-term outcome, but also immediate surgical mortality [39]. Meticulous surgical technique is imperative in brain tumor surgery of infants [39]. The use of bipolar cautery, hemostatic clips, and bone wax is critical during skin, bone, and dural opening. With a midline approach, incision and division should rigorously follow the avascular midline area represented by the ligamentum nuchae. This avascular structure offers the possibility to avoid blood loss and to avoid injury to the muscular layer that, especially in infants, is thin and should be preserved for an appropriate reconstruction during closure. Craniotomy is usually performed with a high speed drill, and two burr holes placed immediately below the transverse sinuses bilaterally 1 cm from the midline are usually sufficient to allow adequate dural dissection on the midline and to start the craniotomy on each side of the posterior fossa. In case of CP angle tumors, the standard craniotomy is usually enlarged with rongeurs asymmetrically to the side of the tumor, enlarging also the opening of the occipital foramen on the same side. At the time of dural opening, great attention should be paid to the midline intradural sinuses that are still well developed in infants since their delayed occlusion can result in profuse

Fig. 4 a Midline skin incision for median and paramedian tumors. b–c BHockey-stick^ skin incision and retromastoid BS^-shaped incision, for tumors extending in the cerebellopontine angle. The retromastoid S-shaped incision is the authors’ preferred incision for tumors with lateral extension (see text)

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bleeding. Bilateral dural opening with midline control is mandatory even in case of giant CP angle ependymomas: in fact, unilateral dural opening would result in inadequate decompression of the posterior fossa structures, leading to cerebellar swelling and herniation and finally resulting in inadequate surgical exposure and significant cerebellar damage. After early biopsy of fresh viable tumor tissue for histology, genetic analysis and cell culture if requested by the authorized treatment protocol, thorough coagulation of the tumor surface prior to debulking, can reduce blood loss. The peripheral supplying vessels are also progressively coagulated to reduce the bleeding from the tumor. Gaining control of the region of the tumor receiving the dominant blood supply in an early phase of the procedure is also useful. Therefore, both Fig. 5 Microscopic features of nodular/desmoplastic medulloblastoma in a 6-month-old baby. a Hematoxylin-eosin, ×10. Medulloblastoma: diffuse pattern. Note the homogenous population of small, round cells with small cytoplasm and dense, packed, uniform nuclei. b Hematoxylineosin, ×20. Medulloblastoma: diffuse pattern. Note the moderate mitotic activity. c: Hematoxylineosin, ×10. Medulloblastoma: nodular pattern. Note the nodular organization of the cellular population with neuronal differentiation, more scattered nuclei and no vascular proliferation (horizontal arrow) compared to the dense cellularity of the classic population (circular selection). d Hematoxylin-eosin, ×10. Medulloblastoma: desmoplastic/nodular pattern. The nodules of cells with neuronal differentiation are organized in desmoplastic stroma. e GordonSweet stain for reticulin fibers ×10. Reticulin fibers typically stain the internodular spaces in nodular medulloblastoma. f Area enlarged from e: reticulin staining is well evident in the perinodular stroma. g Ki 67 staining. Note the hyperexpression of the cellular proliferation index in the internodular spaces filled with less differentiated neoplastic cells if compared to the nodular population with neuronal differentiation. h Synaptophysin staining. Note the staining only in the nodular population with neuronal differentiation and its complete absence in the internodular spaces

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PICAs should be identified at the beginning of the procedure prior to attempt the tumor excision, in most fourth ventricular tumors. In cases of giant CP angle ependymomas, usually resection of the homolateral cerebellar tonsil before approaching the tumor can be extremely helpful in improving vision and decreasing the need for cerebellar retraction in the initial phase of the surgery. Piecemeal removal and internal debulking may result in significant bleeding, and, considering that this bleeding usually stops only when the resection is completed, the removal should be realized as quickly as possible using both microsurgical instruments and ultrasonic aspirator. In case of some highly malignant neoplasms such as

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cerebellopontine angle AT/RT, a safe total removal may be impossible. Staged surgery can be considered, if hemostasis can be achieved. The immediate postoperative course takes place within the ICU. Early neuroimaging investigation (brain MRI with contrast medium administration within 24 h from surgery) is obtained to rule out possible surgical complications and to assess the extent of tumor resection. If the postoperative MRI shows the expected tumor removal and absence of complications, sedation can be stopped and the ET tube removed within a few hours from the end of MRI. If an EVD is present, it is preferably left closed or with the drainage bag at least 20 cm above the external acoustic meatus, in order to avoid excessive drainage and reduce the risk of subdural hygroma. If hydrocephalus does not develop, the EVD is usually removed 4–5 days after surgery.

Chemotherapy In young children with malignant tumors, chemotherapy is used to avoid or delay radiation therapy and its unacceptable consequences: endocrine abnormalities, impaired axial growth, hearing impairment, neuropsychological dysfunction, and second malignancies. Many trials include intensive chemotherapy, followed by myeloablative chemotherapy, reserving radiation therapy for patients with residual or recurrent disease. With this approach, a 3-year event-free survival (EFS) rate of 49 % and overall survival (OS) of 60 % has been reached in disseminated Fig. 6 Nodular/desmoplastic medulloblastoma in a 6-monthold infant presenting with macrocrania, tense anterior fontanel, and Parinaud sign. MRI at presentation showed a inhomogeneous tumor involving the entire vermis, with solid enhancing portions (a axial and b sagittal contrast-enhanced T1 weighted images) and cystic portions, well evident on T2 weighted images (c), associated with hydrocephalus

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medulloblastoma, in children under 6 years of age [7]. This approach is not without risk, and the price to pay is a toxic mortality rate between 5 and 8 %. In cases of highly malignant hypervascularized tumors, safe radical resection is difficult to obtain. A therapeutic strategy using adjuvant chemotherapy followed by second look surgery may decrease the overall size of the tumor and diminish its hemorrhagic potential, offering higher probability of radical resection at second look surgery [7, 39].

Tumor types The frequency of specific tumors varies with age. As reported by Souweidane, reviewing 1185 patients with both supratentorial and infratentorial tumors, the relative frequencies of tumors types in patient diagnosed in the first 2 years of age was astrocytoma (31.6 %), PNET/medulloblastoma (20.5 %), ependymoma (13.3 %), choroid plexus tumor (11.1 %), teratoma (4.6 %), glioneural tumor (1.8 %), and other (17.1 %). At time of birth, the distribution was slightly different: teratoma (30 %), astrocytoma (26.5 %), PNET/ medulloblastoma (20.5 %), choroid plexus tumor (6 %), glioneural tumor (3.6 %), ependymoma (2.4 %), and other (11 %) [39]. No series has specifically focused on posterior fossa tumors. The frequency of posterior fossa tumors in infancy can be only estimated. The most frequent are medulloblastomas, followed by astrocytomas, AT/RT, ependymomas, and brain stem gliomas/gangliogliomas.

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Medulloblastoma Approximately 10–15 % of medulloblastomas are diagnosed within the first year of life. They represent the most common brain tumor in infants. In this age group, medulloblastomas tend to have a worse prognosis, so that, irrespective of extent of disease or presence of dissemination, they are categorized as Bhigh risk^ (as for all children <3 years of age). The cause of the worse prognosis appears not only related to the limitations of radiation therapy, but also to more aggressive behavior of the tumor. Leptomeningeal dissemination occurs in 27 to 43 % of younger children at presentation [39]. Histological subtype and molecular characteristics of the tumor also influence outcome: the presence of widespread anaplasia or large

Fig. 7 Anaplastic ependymoma in 5-month-old infant (same case of Figs. 3a and 4c), presenting with head tilting, hypotonia, and crying. MRI (a–c) showed hydrocephalus associated with a fourth ventricular lesion extending downward until C3 and laterally in the left cerebellopontine angle through the foramen of Luschka. Axial (a) and sagittal (b) contrast-enhanced T1 weighted images and coronal (c) T2 weighted images. The patient underwent ventriculo-peritoneal shunt insertion and total removal of the lesion. d–f Three-month follow-up MRI showing complete resection. The patient underwent chemotherapy. g (axial contrast-enhanced T1 WI) and h (axial T2 DRIVE WI): 1-year

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cell morphology are associated with decreased progressionfree survival. Noteworthy, in infants, nodular/desmoplastic tumors seem to carry a better prognosis [25] (Figs. 5 and 6). The prospective multicenter trial HIT 2000 confirmed the prognostic impact of histology in patients aged <4 years. Desmoplastic/nodular histology was an independent prognostic factor for event-free survival. In this subgroup of children, tumor control was obtained by chemotherapy alone [46]. The survival rate was over 80 %. Over the last decade, genetic studies showed that medulloblastomas are not a single disease entity. Four molecular subgroups of medulloblastoma each with distinct genetic profiles, pathway signatures, and clinicopathological features were identified: WNT, SHH, group 3, and

follow-up showing recurrence of the tumor in the left lateral recess. The patient underwent re-operation, with complete removal of recurrent tumor. The patient developed left facial nerve palsy. i Complete removal of the lesion. The patient was addressed to radiotherapy on the posterior fossa. l:At 22 months from initial diagnosis, the patient developed lumbar metastasis. The patient was operated again with L3L5 laminectomy and complete removal of the lesion and radiotherapy on the lumbar spine. m–o At 4-year follow-up, the patient is alive with no evidence of disease

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group 4 [42]. WNT activation in medulloblastoma is associated with good outcome and immunohistochemistry analysis for nuclear accumulation of β-catenin is a marker of immediate clinical impact for upcoming trials aiming to test the feasibility of reducing therapy intensity in WNTdriven medulloblastoma. SHH and group 4 are generally associated with an intermediate prognosis whereas group 3 with a poor one. No specific molecular subtypes are associated with infantile medulloblastomas. The results of cooperative studies show that survival rates are significantly reduced in younger children. The recent trend in treatment has focused on an attempt to avoid, delay, or reduce radiotherapy with chemotherapeutic supplementation [39]. The extent of surgical resection and degree of metastatic disease appear to influence outcome. Complete surgical resection is not simple to achieve in this age group. In the experience of the

Fig. 8 Microscopic aspects of anaplastic ependymomas (same case of Fig. 7).a Hematoxylineosin, ×40. Features of anaplastic ependymoma. Note the intense cellularity, the perivascular pseudo rosettes (vertical arrows) and calcification (horizontal arrow). b Immunohistochemistry. GFAP staining, ×20. GFAP stains the cytoplasm of tumor cells that are organized in perivascular pseudorosettes around blood vessels (vertical arrows). c Hematoxylin-eosin, ×10. Note the intense hypercellularity, with diffuse perivascular growth pattern. d Hematoxylin-Eosin, ×20. Horizontal arrows delimitate an area occupied by larger and less colored nuclei of endothelial cells that will later organize in blood vessels. Pattern of neovascularity. e Hematoxylineosin, ×20. Anaplastic ependymoma. Arrows outline a large acellular area of necrosis

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pediatric oncology group [8], total resection was performed in 38 %, with an incomplete resection in 62 %. The overall 5-year progression-free survival was 31.8 %. Progressive disease tended to occur early, with most failures occurring in the first 6 months and no cases of progressive disease occurring after 2 years of therapy. The overall survival at 5 years was 39.7 %. The 5-year survival was 60 % for children with gross total resection (GTR) and 32 % in children with subtotal resection. In children with GTR and no metastases, 5-year survival was 69 %. The role of radiation therapy in young babies is debated. In the Canadian series [19], when comparing children more or less than 18 months of age at time of diagnosis, there was a significantly higher survival in the older grouping of children. One factor that may account for this difference is that radiation therapy was significantly more often used for the over 18-month-old patients, and this

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likely affected survival. However, when comparing children less than 18 months who received radiation therapy,

their survival was not different from those under 18 months who did not receive radiation therapy. This

Fig. 9 Classic ependymoma in a 12-month-old child, presenting with drowsiness, irritability, and tilting of the head. Axial (a), coronal (b, c), and sagittal (d) contrast-enhanced T1 weighted images and midsagittal T2 DRIVE MR sequence (e) showing a giant cerebellopontine lesion expanding upward until temporal fossa, downward until C2 and medially through the right Luschka foramen into the fourth ventricle. Postoperative axial (f), coronal (g, h), sagittal (i) contrast-enhanced T1 WI, and sagittal T2 WI (l) showing complete resection of the tumor. Histological examination (m) revealed the classic features of grade II

ependymoma: perivascular pseudorosettes, and tumor cells growing with a diffuse, more uniform pattern if compared to Fig. 6. No necrosis and no neovascularization can be noticed (m Hematoxylin-eosin, ×10). Fig. n Immunohistochemistry (EMA, epithelial membrane antigen staining, ×40). EMA stains the cytoplasm of tumor cells, with a diffuse pattern in the perivascular pseudo rosettes (diagonal arrow) or with a dotlike pattern, associating a more intense perinuclear staining (horizontal arrow) surrounded by a more diffuse cytoplasmic staining pattern (vertical arrows)

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ƒFig. 10

Pilomyxoid astrocytoma in a 4-month-old infant, presenting with vomiting and macrocrania. a Sagittal T2 WI, b axial FLAIR, c axial contrast enhanced T1 WI, and d sagittal contrast-enhanced T1 WI showing a inhomogeneous IV ventricular tumor, originating from the dorsal aspect of the brain stem, expanding in the right lateral recess. A shunt was urgently positioned and a subtotal resection was obtained, leaving a film of tumor on the dorsal aspect of the medulla (e–g). SIOP 2004 protocol for low-grade gliomas was started, but tumor progressed (h sagittal contrast enhanced 4 months following operation and i 1 year following operation). The patient was operated again with near total resection. At 5-year follow-up, the residue of the tumor is stable and the patient neurologically intact (l–n). On microscopic examination, the typical pilomyxoid pattern was evident. o Hematoxylin-eosin, ×10. Scattered cells with large mucinous cytoplasm. p Hematoxylin-eosin, ×20. Limited endothelial proliferation

suggests that perhaps very young children have a biologically different medulloblastoma. Attempts to avoid craniospinal radiation in infants, substituting it with focal radiation of the posterior fossa or tumor bed, resulted in a high rate of distant relapse and failed to demonstrate improved outcome over chemotherapy alone. Therefore, the prevalent tendency is to treat infants with radiationsparing approaches, which have been improved by using dose intensive regimens with or without autologous stem cell rescue. In this strategy, radiation is avoided as firstline approach, reserving it for a salvage treatment. Other groups report different experiences: the COG P9934 study recruited 74 infants with nonmetastatic MB. After initial surgery, the treatment included induction chemotherapy, secondary surgery, 3D conformal RT limited to posterior fossa (18–23.4 Gy) with tumor bed boost (cumulative 50.4–54 Gy), and maintenance chemotherapy. The 4year EFS and OS were 50 and 69 %, respectively. The authors claimed that the addition of 3D conformal RT increased the EFS compared with the use of postoperative chemotherapy alone, without interfering in cognitive or motor function [2]. According to Italian Association of Pediatric Hematology and Oncology (AIEOP) policy, our tendency is to avoid radiotherapy as first-line approach in infant medulloblastomas and treat with dose-intensive regimens of chemotherapy: radiotherapy is delayed as much as possible when complete remission is obtained after surgery and intensive dose followed by highdose chemotherapy. Craniospinal radiotherapy is performed at any age as salvage treatment, as in cases of metastatic disease at presentation where complete remission cannot be obtained after surgery and intensive+high-dose CT, or in case of disease that progresses during chemotherapy treatment. In the recent era, it has been shown that the molecular classification of medulloblastomas outperforms the classical histological stratification and is likely to revolutionize management of patient with medulloblastoma, especially the young patients who are more vulnerable to treatment toxicity [12, 30].

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Ependymomas Ependymomas are the second most common posterior fossa tumor in young children. In infants, they are almost exclusively located in the posterior fossa. Young age at time of diagnosis has been shown to negatively affect outcome. Proposed reasons include a lower rate of complete resection, the avoidance of radiation therapy and biologically aggressive behavior. Although whether pathology is predictive of outcome is controversial, in the first year of life, a higher degree of anaplastic ependymomas can be found, which account for about 50 % in age group (Figs. 7, 8, and 9). The recent genomic classification of ependymomas showed the existence of two separate, well-identified groups of ependymomas [50]. Group A patients are younger, tumors are more frequently located in the CP angle (67 vs 5 %), present a significantly higher recurrence rate (56 vs 25 %), metastasis at recurrence, and death (35 vs 5 %) compared with group B patients. In fact, recurrence rate, metastasis at recurrence, and death rate can be explained by the fact that CP angle ependymoma in younger babies are more difficult to be removed completely in low referral pediatric centers. Nevertheless, in accordance with this classification, one should be at least aware that, when dealing with a CP angle ependymoma below 2 years of age, the surgeon is facing a more aggressive form of ependymoma, with a higher rate of cerebellar invasion (33 vs 5 %). For both reasons (biologically aggressive tumor in a more difficult surgical location), the surgeon has a real surgical challenge and is committed to a radical removal, either in a single or staged procedure [37]. For these reasons, the importance of treating these children from the beginning into a tertiary care high volume referral center by experienced multidisciplinary team cannot be overestimated. Surgical treatment plays an important role in the treatment of ependymoma as the quality of resection represents the main prognostic factor in this disease. Different operative approaches have been described. Most of these tumors arise in the fourth ventricle and can be reached through a transvermian or a telovelar approach. In case of development in the cerebellopontine angle and/or involvement of the spine, the surgical approach is tailored to the location. The presence of extended tumors in both cerebellopontine cisterns, the fourth ventricle, and/or the spine, especially in the youngest, should led the surgeon to staged surgeries. In case of bilateral cerebellopontine cisterns involvement, the surgery should be done in two steps to avoid irreversible lower cranial nerve palsy [32]. It is particularly important to minimize the risk of neurological complications that may be due to removing the tumor from critical locations such as the lower cranial nerves, to avoid tracheostomy and/or gastrostomy. The Pediatric Oncology Group (POG) study [8] evaluated children younger than 3 years with ependymomas, treated with surgery and adjuvant chemotherapy, in order to avoid

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or delay radiotherapy. The extent of resection was the most important predictor of outcome, with 5-year overall survival of 66 and 25 %, respectively, in case of complete, or partial resection. Unlike children with medulloblastomas in whom failures tended to occur early, children with ependymomas developed progressive disease over several years. Therefore, with long-term follow-up, a divergence in outcome between two groups of age (children younger than 1 year and those between 2 and 3 years of age) was evident in the POG study. Survival rate at 5 years was 26 % in younger children and 63 % in older. The conclusion was that a delay of radiation

>1 year adversely affected survival. Considering that the principal site of recurrence is the primary site and that the consequences of radiation therapy to the posterior fossa are limited [47], conformal radiotherapy limited to the posterior fossa or to the tumor bed may be administered also to young children. Controversies however still exist as to whether adjuvant radiotherapy should be delayed in children less than 3 years of age who may be more vulnerable to long-term adverse effects including neurocognitive impairment, endocrinopathies, and sensoneurinal hearing loss. For infant with ependymoma, therapy is particularly challenging; the

Fig. 11 Atypical teratoid/rhabdoid tumor (AT/RT) of the left cerebellopontine angle in a 6-month-old baby girl, presenting with left facial nerve palsy. a–d MRI at presentation (contrast-enhanced T1 WI). e–f Postoperative MRI showing complete resection. The patient could not start chemotherapy because presented varicella. Two months later, MRI

revealed recurrence of the tumor in the cerebellopontine angle (g axial contrast-enhanced T1 WI; h coronal T2 WI; and i axial T2 DRIVE WI). A ventricular catheter connected with an Ommaya reservoir was positioned, and the patient started systemic and intrathecal chemotherapy

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benefit of chemotherapy is no more clear than in older patients [33]. The most promising report of chemotherapy for this age group comes from the Children’s Cancer and Leukemia Group Brain Tumor Committee [14]: incorporation of highdose methotrexate into neoadjuvant chemotherapy, with utilization of RT only on progressive disease, resulted in a 5-year survival rate of 44 %. The AIEOP experience in infant ependymoma demonstrated that infant who received chemotherapy after surgery (vincristine, high-dose methotrexate and cyclophosphamide alternating with cisplatin plus VP16 for 14 months and subsequently with VEC (VCR, VP16, and cyclophosphamide for 6 months) with radiotherapy for residual tumor after the completion of chemotherapy or for progression confirmed poor rates of event-free survival and overall survival for upfront chemotherapy in infant ependymoma. No better neurocognitive outcome was demonstrated in the few survivors who never received RT [26]. Fig. 12 Microscopic features of an infantile AT/RT. a Hematoxylin-eosin, ×40. AT/RT. Note the clear, vesicular nuclei with nucleolus. b Hematoxylineosin, ×60. AT/RT. Note the clear, vesicular nuclei (horizontal arrows) with dense nucleolus (vertical arrows) and clear cytoplasm (diagonal arrow).c Immunohistochemistry. EMA (epithelial membrane antigen) staining, ×20. EMA stains the cytoplasm of tumor cells in a diffuse or dense pattern, and somewhere stains the membrane, with a target-like staining (diagonal arrows). d Immunohistochemistry. Actin staining, ×20. Actin stains the cytoplasm of tumor cells (circle selection) and of endothelial cells outlining the lumen of vessels (horizontal arrows). e Immunohistochemistry. INI1 staining, ×20. INI1 is a nuclear marker that in AT/RT does not stain the nuclei of tumor cells (round selection) (AT/RT is by definition a INI1—neoplasm) but stains the nuclei of endothelial cells (elliptic selection)

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Published results from St. Jude’s Children’s Research Hospital substantiate the use of upfront postoperative RT even in very young patients. In their prospective trial of 153 patients with localized ependymoma under the age of 3 years, adjuvant conformal RT immediately after surgery led to a 7-year eventfree survival (EFS) and overall survival (OS) of 76.9 and 85.0 %, respectively. Neurocognitive outcomes studied in 88 of the above patients were within normal range at or beyond 24 months. Evaluation of functional outcomes in 123 patients who received conformal or intensity modulated RT (mean age at irradiation 4.6 years) up to 5 years after treatment revealed a decline in communication skills index but otherwise stable intelligence quotient (IQ) and adaptive functioning [24, 29]. In accordance with the available data, our policy is an early initiation of adjuvant RT in the multimodal management of pediatric and infant ependymomas. The current COG study ACNS 0831 is exploring in a randomized setting whether post-irradiation maintenance

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chemotherapy using vincristine, etoposide, cyclophosphamide, and cisplatin will improve EFS and OS for newly diagnosed patients without residual tumor following surgical resection [1]. In cases of residual ependymoma, second-look surgery is advocated to achieve gross total resection. In cases of recurrence, surgery and radiotherapy (if not administered before) are indicated. Further research is needed to determine the best regimen for postoperative RT for infant with ependymoma. Studies are on the way to elucidate the role of biomarkers in risk stratification and the use of proton radiotherapy in lieu of conventional RT to reduce adjacent tissue damage. Cerebellar astrocytoma Cerebellar astrocytoma, which is one of the most common posterior fossa tumors in the pediatric population, is relatively uncommon in the first year of life. Cerebellar astrocytomas are usually sporadic, but association with neurofibromatosis type 1, Turcot syndrome, PHACE(S) syndrome, and Ollier’s disease has been reported. Pilocytic astrocytoma is the most frequent histology, while high-grade astrocytomas are exceptional, usually associated with the aforementioned syndromes. A variant of pilocytic astrocytoma, the pilomyxoid astrocytoma, initially described in the hypothalamic and chiasmatic region, can be found also in the posterior fossa. This tumor has a predilection for younger children, with mean age of onset at 18 months. It has higher incidence of brain stem invasion, intrinsic necrotic cavitation, leptomeningeal dissemination, and tumor recurrence (66.7 vs 9.1 % in the series of El Fig. 13 a–d Neonate presenting with left facial palsy and strabismus. MRI showed a large infiltrating lesion of the left brain stem infiltrating the upper, middle, and lower cerebellar peduncle with a large cerebellar component at the level of the lower cerebellar peduncle (b)

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Beltagy [9]). Pilomyxoid astrocytomas (Fig. 10a–o) and its variant intermediate pilomyxoid astrocytomas are classified as grade II tumors. At the current time, pilomyxoid astrocytomas are treated in an analogous fashion to the pilocytic astrocytomas (surgery+SIOP low-grade gliomas protocol in case of brain stem invasion). In the future, with better molecular classification, this therapeutic approach probably will differ [39]. Atypical teratoid rhabdoid tumor Atypical teratoid/rhabdoid tumors (AT/RTs) of central nervous system (CNS) are rare and among the most malignant neoplasms in children younger than 3 years of age. AT/RTs were defined as an entity in 1996 and added to the World Health Organization (WHO) brain tumor classification in 2000. Prior to its recognition as a separate entity, it was often classified as a medulloblastoma, primitive neuroectodermal tumor, or choroid plexus carcinoma. In the more recent series, it represents more than 20 % of CNS tumors in infants [34, 40, 43]. It is an embryonal tumor similar to medulloblastoma, but characterized by the presence of rhabdoid cells and by a specific gene abnormality within the long arm of chromosome 22 (INI1 gene, also known as SMARCB1 or hSNF5). There are reports of patients from the same family who were found to have germ line mutations in one allele of the SMARCB1/INI1 gene, and the remaining allele has been found to be lost within their tumors. This is called rhabdoid tumor predisposition syndrome, an autosomal dominant cancer syndrome predisposing to renal or extrarenal malignant rhabdoid tumors [38]. This tumor has a predilection for posterior fossa and pineal region

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of young children. In the posterior fossa, it tends to occur offmidline and grow into the cerebellopontine angle (Figs. 11 and 12). It is typically large, heterogeneous with cysts, hemorrhage, calcifications, and solid parts with increased cellularity. Approximately 20 % of AT/RT present with disseminated disease at the time of diagnosis. Extra-axial location is not rare and can be extend from posterior fossa to supratentorial. The prognosis is very poor, with a mean postoperative survival of

6–11 months, characterized by early recurrence and CSF dissemination. The treatment is based on multimodal therapy. Mean survival time in infants is 3 months after only surgery and 8 months with adjuvant chemotherapy and radiotherapy. In older children, combination of maximal surgical resection, intensive chemotherapy with or without stem cell support, and radiotherapy (when feasible) appears to offer same

Fig. 14 a One-month-old baby girl, presenting with progressive macrocrania, sunset gaze, and bulging fontanel. Sagittal T1 MRI shows a large enhancing mass invading the posterior fossa and the region of the torcular with significant anterior displacement of the brain stem and cerebellum. Hydrocephalus is evident. b CT scan at admission. Note the contrast enhancement and the hydrocephalus that was treated by endoscopic third ventriculostomy. Open biopsy revealed a mesenchymal sarcoma. c CT at the age of 11 months, following open

biopsy and 10 months of chemotherapy. The lesion proved to be chemoresistant. Note the spotty calcification. d–f MRI scan at the same time of c: no significant reduction in tumor volume. The lesion has invaded the parenchyma of the left parietal lobe (e) and seems to obliterate completely the sagittal sinus (f). g–i MRI performed after subtotal removal. After surgery, the baby was irradiated but the tumor recurred few months later and the patient eventually died

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chances of long survival. Surgery is attempted to obtain a gross total tumor resection; however, this can be achieved in no more than 50–70 % of cases [34, 40, 43]. The infiltrative growth pattern, the frequent involvement of multiple cranial nerves, vascular structures and brainstem, and the large tumor extent are the main reasons limiting the surgical excision. Although there are not conclusive data, initial gross total Fig. 15 Same case as Fig. 11. The histological features are in favor of mesenchymal Sarcoma. (a) Sharp demarcation of the neoplastic mass from the surrounding soft tissue; (hematoxylin and eosin stain, 5x). (b) Loose areas alternating with hypercellular areas, in this field with a perivascular concentration; (hematoxylin and eosin stain, ×10). c Hypercellular areas: epithelioid cells, sometimes arranged in papillary structures (hematoxylin and eosin stain, ×10). d Hypercellular areas: epithelioid cells with mitotic activity (arrow) and some apoptotic bodies (asterisk) (hematoxylin and eosin stain, ×40). e Loose areas: spindle cells, with a clear cytoplasm, arranged in a loose background (hematoxylin and eosin stain, ×40). f Strong cytoplasmic immunoreactivity for vimentin (×40). g High nuclear immunoreactivity for the cellular proliferative index Ki67 (×40)

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resection appears to prolong survival. In the series of Hilden et al., children who underwent a gross total tumor excision (47 %) had both median survival and event-free survival longer than those who received initial partial resection or biopsy (20 vs 15.25 months and 14 vs 9.25 months, respectively) [15]. Encouraging results have been shown using an intensive chemotherapeutic approach that incorporated intrathecal

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methotrexate and cytarabine [16, 39]. Intrathecal agents, administered via an Ommaya reservoir, are useful in tumors with high tendency towards CSF dissemination, especially in infants, in which toxicity of craniospinal irradiation is unacceptable. Cognitive assessment of long survivors of children that underwent intrathecal chemotherapy revealed a reduction cognitive ability compared with age-matched controls, but improvement when compared with historical controls treated with craniospinal irradiation [36]. This aggressive tumor remains a significant challenge in pediatric neuro-oncology, and new therapeutic approaches are needed. Recently, Wetmore et al. [49] reported encouraging data regarding the use of Alasertib, an inhibitor of Aurora Kinase A (AURKA). AURKA encodes a protein that Fig. 16 Six-month-old baby girl with a history of two episodes of meningitis in the last 3 months. MRI showed a small nonenhancing lesion filling the cisterna magna with a small enhancing component adherent to the left lower cerebellar peduncle (a). The dermal sinus tract entering the skull above the torcular and entering the posterior fossa dura below the torcular is evident on sagittal T2 (b). Clinical examination showed the very small outlet of the dermal sinus tract on the occipital midline (c). This was excised during surgery including it within surgical incision (d). The entry point into the bone (e), the intradiploic track (f), and the dural entry point were very well identified at surgery

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regulates the formation and stability of the mitotic spindle and is highly active in AT/RT through loss of the INI1 tumor suppressor gene. The authors demonstrated that Alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. It has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. Radiotherapy, usually craniospinal irradiation because of the high frequency of the disease to disseminate throughout the craniospinal axis, should be delayed until the third year of life. In infants, the radiation fields are usually reduced to local primary tumor volume when there is no proven dissemination to the neuro-axis. Conformal radiotherapy is useful to reduce

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exposure to surrounding critical structures. Proton therapy is a way of utilizing conformal radiotherapy with the physical properties of rapid dose fall-off distal to the target volume. Protons produce little to no exit dose, thus minimizing the exposure of normal brain tissue to ionizing radiation [6]. In a recent study, 10 patients with the diagnosis of AT/RT were treated with upfront local 3D conformal proton therapy [6]. With a median follow-up of 27.3 months, only two patients relapsed, and at the last follow-up, nine patients were alive without the evidence of disease. Other recent larger experience [27, 48] also showed encouraging results of proton therapy in infantile AT/RT of the central nervous system. As this therapeutic option becomes more readily available, it is possible that the overall prognosis of AT/RT, which is extremely dismal at the present time, may be improved, while limiting the long-term side effects of the actual therapeutic regimens. According to the European Rhabdoid Tumor Registry, our policy is to treat patients affected by CNS AT/RT younger than 18 months of age by a combination of neurosurgery, radiotherapy, and chemotherapy regimens. Cytostatic drugs applied were mainly cisplatinum, etoposide, vincristine, ifosfamide, doxorubicin, actinomycin-D, cyclophosphamide, and some intraventricular component. In addition, we consider a second-look surgery after each cycle to obtain a complete local control. If this was obtained, the patient underwent radiotherapy as soon as possible, followed, if stem cells available, by high-dose chemotherapy. Brain stem tumors Brainstem tumors comprise 0.5–1.5 % of all brain tumors diagnosed during infancy [20, 41]. They can be classified as focal exophytic tumors, which typically arise within the dorsal medulla (Fig. 10), cervico-medullary tumors, or diffuse infiltrating tumors, which generally occur within the pons. The latter are almost invariably high-grade gliomas and have a poor prognosis. In the neonate with a brain stem diffuse tumor, fatal respiratory distress usually occurs rapidly [41]. Therefore, treatment of diffuse infiltrating pontine tumors in very young babies is palliative. Surprisingly, some neonatal cases of typical diffuse brainstem gliomas undergo spontaneous resolution, as reported in literature [23, 44], or remained unchanged for a long time (Fig. 13a–d). However, none of these reports, but one [23], included histopathological confirmation of the diagnosis [41]. In older children radiotherapy may lead to neurological improvement. However, 90 % of cases will die of the disease within 2 years from diagnosis. On the contrary, for dorsal exophytic and cervicomedullary tumor surgery is the initial treatment of choice (Fig. 10). Histology of these lesions is usually pilocytic astrocytoma, even if other histology such as pilomyxoid astrocytoma, fibrillary astrocytomas, and gangliogliomas are more frequent in the first year of life than in older children. The

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mainstay of treatment is surgical debulking, followed by close observation. Chemotherapy and radiotherapy are reserved for progressive lesions [21]. Rare tumors and main differential diagnosis Exceptionally, tumors may arise from the bone, dura, or soft tissues and develop within the posterior fossa. These lesions can be extremely challenging, especially if congenital, because of the very large dimension they can reach. In small babies, staged resection is certainly advised, and the correct strategy usually includes safe control of hydrocephalus if present, large biopsy, test the chemosensitivity of the lesion, then continue an effective chemotherapy protocol until obtaining reduction or stabilization allowing the child to grow, then approach the lesion for a radical resection if anatomically possible. The use of radiotherapy can be discussed even at a young age in case of soft tissue tumors, when the combination of chemotherapy and surgery has allowed a complete removal (Figs. 14 and 15). Differential diagnosis of neonatal posterior fossa tumor should include dermoid cyst associated with a dermal sinus tract. In these cases, the clinical history is usually pathognomonic, clinical examination reveals the dermal defect in the midline, sometimes associated with purulent discharge, and MRI is usually able to demonstrate the dermal sinus tract connecting the skin to the intracranial mass that has typical radiological features (Fig. 16).

Conclusions Posterior fossa tumors in newborns and infants remain a very challenging condition. The overall prognosis remains dismal because of the prevalent aggressive histologies, the surgical challenges, and the limitations of adjuvant treatment, particularly radiotherapy, available in this age group. Nevertheless, the impressive improvements of anesthesiology and surgical standards allow, in the vast majority of the cases, complete removal of the lesions with minor sequelae in high-volume referral pediatric centers. Moreover, adjuvant chemotherapy may allow significant reduction of tumor volume and vascularity if upfront complete resection is impossible, thus facilitating staged and delayed complete resection. High-dose chemotherapy can be extremely effective in some histologies in controlling the neoplastic disease, delaying recurrences and helping to reach an age where radiotherapy can be safely administered. Finally, genomic subdivision in the very near future will allow identification of subgroups of patients where adjuvant treatment can be effectively tailored in order to decrease the treatment related toxicity.

Childs Nerv Syst (2015) 31:1751–1772 Conflict of interest All authors declare no conflict of interest.

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