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CLINICOPATHOLOGICAL CONFERENCE
PEDIATRICS
CASE:
This is a case of B.Y, a 10-year-old male who was admitted at the Pediatric ICU due to
complaints of intermittent headache of 1 year duration. His vague frontal headaches would occasionally
occur twice a week, usually in the late afternoons. Rest and intake of Paracetamol would relieve pain. A
consultation was done which diagnosed him to have Iron Deficiency Anemia and was prescribed with
oral Iron preparation which he compliantly took. His headaches later on became severe and were
accompanied by projectile vomiting of non-villous, non-bloody vomitus amounting to half a cup that
occurs 2-3 times a day. At another consultation, he was prescribed with Mecklizine 1 tablet TID and
Ibuprofen 1 tablet q4, and was referred to an ophthalmologist. He did not experience tinnitus, gait
disturbance, gastrointestinal, and urinary problems.
The patient has a known allergy to shrimp and was diagnosed with asthma last 2007. He has a
paternal and maternal history of diabetes mellitus and hypertension.
On physical examination, the patient was awake, ambulatory, conscious, coherent and not in
distress. He has normal vital signs with warm moist skin with good turgor. He was found to have slightly
pale conjunctivae. Neurological exam revealed the patient to be in GCS 15 (E4V5M6), positive for
Romberg’s sign, no motor or sensory deficit, negative for Babinski sign, ankle clonus, nuchal rigidity,
Kernig’s sign, and Brudzinski sign. The rest of the physical exam was unremarkable.
COURSE IN THE WARDS
On the first hospital day, the patient was given Omeprazole, a proton-pump inhibitor at 40 mg IV
OD was given to prevent irritation of the esophageal mucosa which may lead to erosive esophagitis due to
multiple bouts of vomiting. Vomiting that is projectile in character warrants investigation of increased
intracranial pressure and immediate intervention should be done since neurological sequalae are likely
with this symptom due to possible intracranial herniation. This explains why the patient was given
mannitol at 100 cc q6h. Mannitol is an osmotic agent that creates an osmotic gradient to cause egress of
water from the brain extracellular (and possibly intracellular) compartment into the vasculature, thereby
decreasing intracranial volume. Dexamethasone, a glucocorticoid, is indicated for the treatment of
vasogenic edema associated with brain tumors but not for edema due to stroke. Although the precise
mechanisms of the beneficial effects of steroids in this practice are unknown, steroids decrease tightjunction permeability and, in turn, stabilize disrupted BBB (Bhardwaj et al). A ventricular tap is used for
the removal of CSF in the management of life-threatening increased ICP associated with hydrocepahalus
(Kliegman et al) as well as cerebrospinal fluid analysis. Imaging studies done were a chest plain
radiograph imaging and a cranial CT scan. The chest x-ray was taken for baseline reference while cranial
CT scan was taken to determine any lesion in the brain that might be causing the increased intracranial
pressure.
On the fourth hospital day, the patient underwent an operation which likely is a surgery to remove
the offending cause and in this case, a medulloblastoma. Limited lateral eye movements on the left that
were noted which may be due to the surgery performed. After the resolution of vomiting, the IV
preparation of omeprazole and dexamethasone were shifted to oral preparation since the patient can
already maintain gastric contents. MRI of the whole spine and liver function test were probably done to
evaluate for possible metastasis from the medulloblastoma.
DIFFERENTIAL DIAGNOSES
EPENDYMOMAS
Ependymomas account for 9-10% of all childhood primary CNS tumors [pizzo, nelson]. Ninety
percent of these are intracranial and 67-70% of these occur in the posterior fossa [pizzo, nelson]. The
highest incidence occurs in the first 6 [nelson] to 7 [seer] years of life. Ependymomas are the third most
common type of brain tumor in children following astrocytoma and medulloblastoma. They are relatively
rare. Recent studies support a male-female ratio of between 1.3 and 2.0 [pizzo].
Ependymomas are tumors that arise from the cells lining the ventricles and the central canal
within the spinal cord. The WHO classified ependymomas in to four types, namely: myxopapillary
ependymomas, subependymomas, ependymomas and anaplastic ependymomas. Symptoms occur
depending on the location of the tumor. Posterior fossa ependymoma or the classic ependymoma are
fairly well delineated tumors that can arise anywhere in the central nervous system. The tumor tends to
grow relatively slowly and displaced, rather than invade adjacent brain or spinal cord tissue. They grow
outside the ventricle through paths of least resistance within the brain. Posterior fossa ependymomas
spread to other parts of the brain or spinal cord through the CSF. They rarely metastasize to sites outside
of the central nervous system.
The epidemiological data stated earlier suggests that ependymoma is a possible differential in B.
Y.’s case since he is a male and is within the age group. It should be noted however that his signs and
symptoms occurred when he was 9 which is 2-3 years off the peak age of incidence. The signs and
symptoms of an ependymoma are dependent on its location in the CNS. The three major locations are the
posterior fossa, supretentorium and the spinal cord. In children, about 90% arise within the brain in the
posterior fossa, in or around the fourth ventricle. Tumors that arise on the floor of the fourth ventricle are
associated with torticollis and ataxia. Posterior fossa tumors may lead to cerebellar dysfunction, resulting
in balance and gait disturbances that frequently are associated with vomiting and lower cranial nerve
finding such as diplopia, facial weakness, tinnitus, vertigo and hearing loss. In this case, we assume that it
is in the cerebellum since it was shown in the CT scan. As to the signs and symptoms, there is no
pathognomonic clinical finding to diagnose an ependymoma or any childhood brain tumor [pizzo]. In
general, space occupying lesions can present with the symptoms that our patient presented with including
vomiting and headaches. If this is indeed ependymoma, it may obstruct the fourth ventricle and lead to
increased intracranial pressure. Vomiting may be extreme with ependymoma because of the involvement
of the emetic chemoreceptor on the dorsal medulla (area postrema) that protrudes into the fourth
ventricle.
This diagnosis is less likely due to lack of cerebellar involvement on the patient. Cerebellar
dysfunction is common due to the location of the tumor, in the posterior fossa. Balance is commonly
affected such as gait disturbances and lower cranial nerve affectations such as diploplia, facial weakness,
tinnitus, vertigo and hearing loss. It is also less likely due to the timing of headache. The patient presents
with headache that is worse in late afternoons. Headache of increased ICP is pain present in upon rising,
relieved by vomiting and gradually decreasing during the day. A CT scan done on the patient revealed a
slight enhancing heterogenous hyperdense lesion is least likely of ependymomas. Ependymomas typically
appears as hyperdense and homogeneously contrast enhancing lesion.
HEMANGIOBLASTOMA
The patient is presenting with cerebellar signs including nystagmus and weakness of the lower
extremities. One of the possible causes of cerebellar lesions is Hemangioblastoma. Hemangioblastoma is
a benign vascular neoplasm which is commonly found in the central nervous system and in most cases it
is found in the posterior cranial fossa. Although considered rare, it is the most common posterior fossa
tumor in the adult population. It has a sexual predilection to males and can develop at any ages but with
low incidence in the pediatric age group. Hemangioblastoma is a solid tumor, usually cherry red in color,
which usually grows in the parenchyma of the organ affected. Cerebellar lesions may present with
cerebellar dysfunction such as ataxia and may produce symptoms associated with increased intracranial
pressure such as headache and vomiting due to hydrocephalus. It usually presents with a long history of
neurological symptoms like headache and is usually followed by sudden exacerbation. In CT scan, it is
seen as a hypodense mass with associated hydrocephalus.
CRYPTOCOCCOMA
The patient presented with intermittent frontal headache and projectile vomiting of 1 year
duration. Significant data from the neurologic examination include (+) horizontal nystagmus and
hyperreflexive lower extremities. Other P.E. result was unremarkable. The chronicity of the patient's
symptoms along with the aformentioned P.E. results, lead to consideration of a possible cerebellar fungal
granuloma formation or a cerebellar cryptococcoma. Cryptococcoma is an infection caused by yeast like
fungus, Cryptococcus neoformans. It occurs due to inhalation of fungus into the lungs which may lead to
a hematogenous spread to the brain. While association is made between fungal infection and the host's
immune status, cryptococcoma can present in patients with no known history of immunosuppression and
no clinical signs of infection. The latter may explain the patient's absence of fever. Intermittent headache
and projectile vomiting are manifestations of increase intracranial pressure due to the mass effect of the
granuloma and edema formation or simply a block on the drainage of the CSF. CSF analysis of the patient
also revealed 100% lymphocytes which is consistent with cryptococcoma patients which presents with
lymphocytic pleocytosis. Diagnostically, this can be difficult to distinguish from a brain tumor, hence,
may also present with an enhancing hyperdense lesion with adjacent edema and mass effect. However,
this was ruled out since CSF analysis was unremarkable for a cryptococcal etiology. Furthermore, post
surgical improvement with this disease is noted with administration of IV Amphotericin B, which was not
given to the patient. He improved with intake of an antibiotic.
PRIMARY DIAGNOSIS
MEDULLOBLASTOMA
Medulloblastoma was chosen as the primary impression for the patient's case because it is
considered as the most common malignant hyperdense brain tumor arising in the cerebellar vermis seen
especially in children, 0-14 years of age. As the tumor grows, it compresses the ventricles causing
obstructive hydrocephalus and increasing the intracranial pressure which caused the projectile vomiting.
The headache was due to the compressive lesion and inflammatory mediators present in the brain.
Medulloblastomas usually takes months or even years to be diagnosed because of its subtle symptoms
which includes non-localized or vague headache, vomiting (due to increased intracranial pressure) and
ataxia found in majority of the patients, however, it was not manifested in the present case. Direct
impingement of the tumor to the brainstem, midbrain and pons could also cause cranial nerve deficits
such as hearing loss and difficulty in eye movement as seen with the patient.
Normal laboratories also helped us on ruling out the other suspected diagnosis and in considering
medulloblastoma as the primary impression. Infectious causes like Tuberculum, Brain abscess and
Meningitis were ruled out because of normal RBC, WBC and Glucose in the CSF. Normal Findings in the
liver also ruled out encephalopathy as the cause of the patients symptoms. Normal kidney function and
the absence of hypertension also ruled out the suspicion of renal and systemic problem that could be the
cause of the patient's manifestation. In addition, there was also no history of trauma which can present
with the same symptoms as the patient. Further, blood chemistries were all normal ruling out a metabolic
cause leaving the group with tumor as the etiology of the disease.
Incidence
Medulloblastoma accounts for 90% of embryonal tumors. It is a cerebellar tumor occurring
predominately in males and at a median age of 5–7 yr. Although predominantly a pediatric tumor,
medulloblastoma can also affect patients of any age from neonates to the elderly. Three quarters of all
cases occur in children, with a median age of 9 years. It is relatively rare, accounting for less than 2% of
all primary brain tumors and 18% of all pediatric brain tumors. More than 70% of all pediatric
medulloblastoma are diagnosed in children under age 10. Very few occur in infancy or under age 1.
The majority of tumors occur in the midline cerebellar vermis. However, older patients may also
present with tumors in the cerebellar hemisphere.
Signs and Symptoms
Patients present with signs and symptoms of increased intracranial pressure (headache, nausea,
vomiting, mental status changes, and hypertension) and cerebellar dysfunction (ataxia, poor balance,
dysmetria). As the pressure in the brain increases due to a growing tumor or blocked fluid passages, the
headaches, vomiting and drowsiness may increase. Other symptoms depend on the nerves and brain
structures affected by the tumor. Since medulloblastomas appear in the cerebellum, the center of balance
and movement, problems with dizziness and coordination are common. Tumors growing close to the
brain’s fourth ventricle may expand into that cavity, blocking the normal flow of cerebrospinal fluid. This
can result in hydrocephalus which is the buildup of cerebrospinal fluid within one of the cavities of the
brain. The pressure of this buildup triggers the tumor’s characteristic symptoms: morning headaches,
nausea, vomiting and lethargy.
Standard clinical staging evaluation includes MRI of brain and spine, both preoperatively and
postoperatively, as well as lumbar punctures.
Etiology and Pathogenesis
Medulloblastomas occur in the posterior fossa. Cytogenetic and molecular genetic studies have
demonstrated multiple abnormalities in medulloblastoma. The most common cytogenetic abnormality
involves chromosome 17p deletions. Molecular studies have identified these lesions as the most common
molecular defect in medulloblastoma, occurring in 30–40% of all cases. It is said that these deletions are
not associated with TP53 mutations. In 10–20% of medulloblastoma cases, genetic material losses are
noted on chromosomes 1q and 10p. In approximately 10% of cases, abnormalities of 9p have been
detected.
It is also currently thought that medulloblastoma arises from cerebellar stem cells that have been
prevented from dividing and differentiating into their normal cell types. This accounts from the varying
histologic variants seen on biopsy. Both perivascular pseudorosette and Homer-Wright rosette formation
are highly characteristic of medulloblastoma and is seen in up to half of the cases.
In addition, molecular genetics reveal a loss of genetic information on the distal part of
chromosome 17, distal to the p53 gene, possibly accounting for the neoplastic transformation of the
undifferentiated cerebellar cells. Medulloblastomas are also seen in Gorlin syndrome as well as Turcot
syndrome.
Diagnostic Procedures
The diagnostic tests, procedures and results for the diagnosis of medulloblastoma are divided into
Laboratory studies (CBC, electrolytes and liver and renal function tests), Imaging studies (CT scan, MRI,
and bone scan), other procedures are audiography or brainstem auditory-evoked response [BAER]),
Lumbar Puncture, Bone marrow aspirate and biopsy and histologic study of the specimen.
Laboratory Studies
The routine laboratory tests mentioned above are primarily for pretreatment evaluation. CBC may
show a substantial reduction of the absolute lymphocyte count (Tadanori et al). The other tests are
primarily to rule out other conditions and gauge the pretreatment health status of the patient.
Imaging Studies
CT scanning of the head, with and without contrast, has more than 95% sensitivity for the
detection of brain tumors. CT plates in patients with medulloblastoma may show prominent
hydrocephalus and a solid, homogeneous, isodense to hyperdense, contrast-enhancing, midline cerebellar
mass. The findings are characteristic though not diagnostic/specific of medulloblastoma.
Head and spinal MRI with and without gadolinium should be performed in all patients with CT or
clinical findings consistent with medulloblastoma and can be useful in such instances by better
demonstrating the anatomic origin and extent of tumor. In addition, Spinal MRI is the most sensitive
method available for detection of spinal cord metastasis. It is also used to detect residual disease
following surgical resection.
Plain film correlation is useful; in asymptomatic patients especially because Medulloblastoma can
metastesize outside the CNS, especially to bone.
Histologic Findings
Medulloblastomas are undifferentiated embryonal neuroepithelial tumors of the cerebellum. They
are highly cellular, soft, and friable tumors composed of cells with deeply basophilic nuclei of variable
size and shape, little discernible cytoplasm, and often-abundant mitoses. These characteristics give the
microscopic appearance of a small, round, blue cell tumor.
Homer-Wright rosettes (ring-like accumulations of tumor cell nuclei around a neuropil-containing
or fibrillary core) and pseudorosettes are variably present. These tumors express neuronal and
neuroendocrine markers, including synaptophysin and neurofilament proteins.
Various degrees of glial or neuroblastic differentiation are noted, suggesting that the primitive
cell of origin possesses the capacity for bipotential differentiation. A histologic variant with abundant
stromal component, desmoplastic medulloblastoma, occurs dominantly in the lateral cerebellar areas of
adolescents and adults. Another more recently described variant is characterized by marked features of
anaplasia that is associated with MYCC oncogene amplification.
Other test like baseline hearing test (audiography or brainstem auditory-evoked response
[BAER]) is recommended because of the potential toxicity from radiation and chemotherapy. Again due
treatment and its possible toxicity, other tests such as echocardiography, pulmonary function tests, or
other more specific tests, are opted for the purposes of monitoring treatment-related toxicity. Lumbar
puncture, CSF cytologic examination is useful for the detection of microscopic leptomeningeal tumor
dissemination. Funduscopic examination (or CT or MRI) must be performed before lumbar puncture (LP)
to rule out the presence of hydrocephaly. In known cases of medulloblastoma, LP generally is deferred
until 2 weeks post-operation to avoid the presence of tumor cells that have disseminated as a result of
surgery.
Treatment
Removing as much tumor as possible is the most important step in treating medulloblastoma.
There are three goals for the surgery: (1) to relieve cerebrospinal fluid buildup caused by tumor or
swelling; (2) to confirm the diagnosis by obtaining a tissue sample; and (3) to remove as much tumor as
possible with minimal neurological damage. Several studies have shown the best chance for long-term
tumor control is when all of the medulloblastoma visible to the naked eye can be removed safely. While
the goal is to eliminate the tumor, some medulloblastomas cannot be removed completely. In one-third of
patients, the tumor grows into the brain stem, making total removal difficult because of potential
neurological damage. If the tumor is determined to be inoperable, a biopsy may still be done to confirm
the diagnosis.
Glucocorticoid treatment decrease the volume of edema surrounding brain tumors and improve
neurologic function- Dexamethasone (initially 12–20 mg/d in divided doses PO or IV) is used because of
its relatively little mineralocorticoid activity. However, due to the toxicities of long-term glucocorticoid
administration, the dexamethasone dose is rapidly tapered to the lowest dose that relieves symptoms.
Occasionally, a ventriculostomy is done to divert excess cerebrospinal fluid from the brain. A
permanent shunt, a long catheter-like tube that drains fluid from the brain to the abdomen, is sometimes
necessary. In most cases, however, removing the tumor opens the cerebrospinal pathways, which restores
both normal fluid flow and pressure. It also eliminates the need for a shunt or drainage device. Within two
days following surgery, an MRI will be done to visualize the amount of remaining tumor. The amount of
remaining tumor will be a strong factor in determining further treatment.
Following surgery, medulloblastoma is usually treated with radiation therapy. It is an important
because microscopic tumor cells can remain in the surrounding brain tissue even after surgery has
successfully removed the entire visible tumor. Since these remaining cells can lead to tumor re-growth,
the goal of radiation therapy is to reduce the number of left-over cells. An additional dose or boost of
focal irradiation to a single or large metastasis may also be administered.
For children with
medulloblastoma, chemotherapy is used to reduce the risk of tumor cells spreading through the spinal
fluid. Children with high-risk medulloblastoma receive full-dose cranial-spinal radiation with
chemotherapy during and after radiation therapy.
For infants under the age of 3, chemotherapy is used to delay or even eliminate radiation therapy.
Cyclophosphamide, vincristine, cisplatin, etoposide, carmustine, procarbazine, cytarabine, and/or
hydroxyurea are used.
In cases that presents with seizures, treatment is identical to the treatment of other forms of partial
epilepsy. The first-line agents phenytoin, carbamazepine, and valproic acid are equally effective;
leviractam and oxcarbazepine are also coming into wide use. It is common practice to administer antiepileptic drugs prophylactically to all patients with supratentorial brain tumors, although there are no
good data supporting this practice.
REFERENCES:
Bhardwaj A, Raslan A. Medical Management of Cerebral Edema. Neurosurg Focus.
2007;22(5):E12
Braunwald, E., Fauci, A., Kasper, D., Hauser, S., Longo, D., Jameson, J., Lozcalzo, J.,
Harrison’s Principles of Medicine. 17th ed. Volume 2. 2008.
Del mundo, Fe. Textbook of Pediatrics and Child Health
Brown, R., Ropper, A. Adams and Victor’s Principles of Neurology 8th Edition. 2005
Kliegman R, Behrman R, Jenson H, Stanton B. Nelson Textbook of Pediatrics, 18th Edition.
2007.
Pizzo P, Poplack D. Principles and Practice of Pediatric Oncology, 4th Edition. 2001.
http://emedicine.medscape.com
http://emedicine.medscape.com/article/341293-imaging#CTSCANFindings
Tadanori Tomita, MD; Mario Ammirati, MD. Reduction of Absolute Lymphocyte Count in
Children With Recurrent Medulloblastoma
CLINICOPATHOLOGICAL
CONFERENCE
PEDIATRICS
Durante, Faida
Esperon, John Richard
Espino, Raziel Vina
Fernando, Emmaline
Figuracion, Julie Ann
Flores, Gian Carlo
Fong, Kathleen
Francisco, Jeff-Ray
Francisco, Reinard
Garcia, Jennifer
Garcia, Marla Marie
Garcia, Maria Regina
Garcia, Roman Karlo
Garcia, Winona Kimmy
Garimbao, Julius France