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Medulloblastoma


The term medulloblastoma originated in 1925 when Bailey and Cushing reported clinical and pathologic features in 29 patients with "a very cellular tumor of a peculiar kind." Most of these 29 patients were children, and the tumors were usually located in the cerebellar vermis over the roof of the fourth ventricle. They also reported seeing five other patients with similar tumors in the cerebellar hemisphere which they thought were "unquestionably of the same histogenesis." They thought that the tumor represented a subtype of glioma and coined the term spongioblastoma cerebelli to describe it. Globus and Strauss, however, used the term spongioblastoma multiforme for a different type of malignant central nervous system tumor, and a confusion of terms resulted. Bailey and Cushing at first considered changing the name of their reported tumor to undifferentiated spongioblastoma, but finally settled on the name medulloblastoma to avoid further confusion. Since then, many reports have appeared in the literature describing this tumor and the name medulloblastoma has remained firmly entrenched in the classification of tumors of the central nervous system.

Medulloblastomas have long been recognized as one of the most common tumors in the posterior fossa and account for 4 to 10 percent of primary brain tumors. In patients under the age of 20, they account for between 15 and 20 percent of central nervous system (CNS) tumors. It is known that the incidence of CNS tumors in children is 2.1 per 100,000 population. Medulloblastoma affects boys more often than girls, with a ratio of between 4: 3 and 2: 1. They most commonly occur in the first decade, with 70 percent of tumors occurring in patients less than 8 years of age. However, medulloblastomas have been reported from the newborn period to the seventh decade.

The total incidence for pediatric tumors in the posterior fossa was reported to be 54.7 percent. Although most of these masses were astrocytomas, between 12 and 15 percent of all pediatric brain tumors are medulloblastomas, midline, but sometimes they present laterally in the cerebellar hemisphere. The tumor may be visible between the tonsils or may lie completely within the fourth ventricle. In many cases the tumor is intimately attached to the anterior medullary velum or the region of the aqueduct of Sylvius or the floor of the fourth ventricle. It is usually reddish and friable and often has a pseudocapsule, some tumors are vascular, others are necrotic. In 15 percent of cases there is evidence of recent or old hemorrhage within the tumor. Diffuse thickening of the arachnoid by tumor spread is occasionally seen over the tonsils and cerebellar hemispheres and is referred to in the literature as sugar coating.

Histologically. the medulloblastoma is a highly cellular tumor, consisting mainly of small. pear-shaped or round cells with round to oval hyperchromatic nuclei and little cytoplasm. The cellular borders are poorly defined. A large number of mitoses are commonly observed in the microscopic field along with occasional rosettes of the Homer-Wright type. suggesting neuroblastic differentiation. On close examination, the cells forming the rosettes are carrot-shaped and mostly have tapering unipolar processes. but they are occasionally bipolar. Sometimes neurofibrils can be demonstrated with silver stains, and differentiation toward ganglion cells, spongioblasts, astrocytes and even oligodendroglia can be seen. These tumors are not usually very vascular, and blood vessels are not a prominent feature of the histologic picture.

A subtype of medulloblastoma is the desmoplastic medulloblastoma, said to be more common in older patients, particularly those over the age of 20. These tumors are located laterally in the cerebellar hemisphere more often than in the vermis or fourth ventricle. They are made up of islands of cells surrounded by a network of fibrous and connective tissue. The cells in the islands are small and round to oval, with the nucleolus sometimes visible. Cytoplasm is scant, and there may be distortion of the cells because of compression by the connective tissue element. In a review of 201 cases of medulloblastoma by Chatty and Earle, were believed to comply with this description of desmoplastic medulloblastoma, and 159 were of the classic type. The patients in the desmoplastic group had an average survival of 51 months, while those with the classic type of tumor had an average survival of 18 months.

Controversy still exists among different schools of neuropathology regarding the cell of origin of medulloblastoma. In 1925, Bailey and Cushing outlined their concept of brain tumor classification based on the cell of origin. They hypothesized a primitive cell-the primitive medullary cell or neuroepithelial cell-which could differentiate into five different cell types: choroidal epithelium, pineal parenchymal cells, primitive spongioblasts, medulloblasts, and polar neuroblasts. According to this idea, the medulloblast was a sort of extraembryonic cell distinct from the spongioblast and neuroblast yet capable of differentiation along both lines. Bailey and Cushing thought this primitive medulloblast was the cell that gave rise to the medulloblastoma. However, there is justification for the view that medulloblastoma originates from the germinative cell, which is derived from the external granular layer of the cerebellum and is capable of bipotential differentiation. This view was suggested by Kershman in 1938 and by Fujita et al. in 1966. Another theoretical possibility is that medulloblastomas are really cerebellar neuroblastomas derived from young neuroblasts, a view supported by the work of Tola and others. Because of the well-known tendency of medulloblastomas to differentiate along spongioblastic and glial, rather than neuronal, lines, however, it has been suggested that this tumor is quite distinct from neuroblastoma and conceivably does not derive from the external granular layer at all. Finally, Rorke has suggested that the medulloblastoma is essentially a primitive neuroectodermal tumor (with or without glial differentiation, neuronal differentiation, or multi- or bipotential differentiation), which is located in the cerebellum.



Clinical Features


Because the fourth ventricle is the preferred site of medulloblastomas, the most common presenting clinical signs are those referable to increased intracranial pressure owing to obstruction of the flow of cerebrospinal fluid and resulting hydrocephalus. The typical history is one of lethargy, headaches, and vomiting, occurring at first rarely but later every morning upon awakening. The predominance of morning symptoms is explained by the fact that intracranial pressure rises during the night as a result of position, decrease in the reabsorption of cerebrospinal fluid, and elevation of PaCO2. As the blood volume increases, the intracranial volume increases and raises the intracranial pressure. Upon awakening, the patient complains of severe headache and may vomit, inducing hyperventilation and a decrease in the PaCO2. Also, as the patient assumes an upright position, there is an increase in venous return and a secondary decrease in intracranial pressure. The child feels better and is able to return to normal activities, and because of this the symptoms are typically dismissed as psychogenic in nature, resulting in delay in diagnosis of the tumor.

If these early symptoms do not lead to a neurological examination and diagnosis of the tumor, they tend to progress to gait ataxia, nystagmus, and, on occasion, cranial nerve palsies, particularly of the sixth and the fourth nerves. When the tumor is located eccentrically and not in the vermis or the fourth ventricle, the patient presents with unilateral cerebellar signs. The duration of the symptoms before a diagnosis is made varies from a few days to as long as 3 to 4 months. with a median duration of 6 to 7 weeks.

On neurological examination. the single most important and most common finding is bilateral papilledema. In many cases papilledema is so severe as to produce marked central scotomas and may progress to severe loss of vision and blindness. In more advanced cases, ataxia, nystagmus, past pointing and cranial nerve palsies are found. In the younger child, percussion of the skull produces a hyperresonance described as the cracked-pot. or Macewen's, sign. Some of these patients present to the paediatrician with an acute ictus suggesting subarachnoid hemorrhage due to spontaneous bleeding within the tumor bed. In 15 percent of all nontraumatic spontaneous subarachnoid haemorrhages were due to a tumor, and of these, almost half were tumors in the posterior fossa, most commonly medulloblastoma. Occasionally, patients have presented with symptoms of spinal cord compression or hemispheric signs, which were later found to be due to cerebral metastases of a previously undiagnosed fourth ventricle medulloblastoma.

The clinical picture should quickly lead to radiologic studies. The plain skull films may show separation of the sutures in patients under the age of 15, and computed tomography makes the diagnosis of mass lesions with uncanny precision. In 97 percent of brain tumors were demonstrated by computed tomography, and the indicated histologic character of the masses was correct in over 80 percent. Magnetic resonance imaging (MRI) of the brain without and with gadolinium enhancement is the diagnostic test of choice, because it not only precisely determines the tumor location but also helps the surgeon to plan the surgical approach and gives warning of possible problems with tumor infiltration or extension into surrounding structures.



Surgical Treatment


Controversy still exists regarding the initial management of the patient with a medulloblastoma. Some groups advocate routinely shunting the hydrocephalus as the first step, claiming that there is lower morbidity and mortality and a better surgical field after the intracranial pressure is relieved for a period of several days to a few weeks. The proponents of this initial step are divided over the need to insert a filter in the shunting system to prevent the spread of tumor cells to the peritoneal cavity or systemically, since, in some studies, an incidence of up to 19 percent of extracranial metastases was reported after shunting. Other groups claim that this is an extremely rare occurrence and see no need for filters in the shunting system. Certainly, when filters are used. it can be expected that there will be a large incidence of shunt malfunction, because the filters tend to clog rapidly with tissue debris. Because of this, recent efforts have been made to develop a shunt with a bypass system that can be opened or closed at will. Another problem with early shunting is that decreasing the pressure in the supratentorial system by draining the hydrocephalus can produce an upward herniation of the tumor, necessitating emergency decompression of the posterior fossa and removal of the mass. This com­plication has been reported in up to 4 percent of all the patients treated initially with shunts. In the authors' experience. shunting for hydrocephalus in patients with medulloblastoma has been nec­essary in only a relatively small number. roughly one-third. For these reasons. it is the Children's Hospital policy not to shunt initially but to treat the patient presenting with increased intracranial pressure secondary to a suspected medulloblastoma with large doses of corticosteroids (dexamethasone once daily in a dosage of I mg/kg : for a period of 2 to 3 days before surgical intervention. This course usually produces a remarkable improvement in the symptoms. and often the results of neurological examination will revert to normal.

Surgery was usually performed with the patient in the prone position and was preceded by the placement of a posterior parietal burr hole and external ventricular drainage. When there is hydrocephalus, a ventricular catheter was inserted subcutaneously into the lateral ventricle, it can, if necessary, be converted to a formal shunting device. The prone position allowed good visualization of the region of the cisterna magna, foramen of Magendie, and fourth ventricle and in many cases obviated the necessity of splitting the vermis itself. A posterior fossa craniectomy was commonly performed, including the rim of the foramen magnum: if necessary, the posterior arch of C1 is easily excised. Frequently the tumor is visible in the cisterna magna upon opening the dura mater. Occasionally, "sugar coating" of the cerebellum and arachnoid can be seen.

Starting from 1980 the setting position got common acceptance to reach the posterior fossa. The head is fixed with Mayfield or other devices connected to the table and adapted to be used to fix the Hallo ring with self-retaining retractors. There is no necessity for Swan-Ganz or subclavian line and there is no need for arterial line. More than 90 cases during the 26 years period with medulloblastomas, no air embolism or other complications got place. During dissection of the soft tissues of the occipital bone, special attention is paid for the venous channels and they are waxed immediately to prevent air embolism. In the absence of tonsilar herniation, an osteoplastic craniotomy is achieved with the pedicle attached to the ligamentum flavum between the posterior rim of the foramen magnum and C1. During bone flap rotation, the lateral edges of the posterior rim of foramen magnum must be thinned, so that it cracks with ease. The flap is then reflected posteriorly abutting the C2 spinous process. In cases of downward migration of the tumor below C2, then the flap is removed and further laminectomy of C1 and C2 is performed as required. In all cases, it was possible to achieve gross total resection of the medulloblastoma.

The surgical goal is to perform total gross removal of the tumor, which can frequently be done in a piecemeal fashion, avoiding traction on the vital structures of the brain stem and cerebellar peduncles. The use of bipolar coagulation, magnification, self-retaining retractors, a high-frequency ultrasonic aspirator, and a laser has greatly improved the chances of obtaining satisfactory removal of the tumor without damage to the surrounding structures. After the tumor is removed, the floor of the fourth ventricle is inspected for infiltration, and cerebrospinal fluid is readily seen draining from the dilated aqueduct of Sylvius.

The surgical plan is always to try to perform a gross total removal; there is evidence in the literature, that this result will enhance the likelihood of long-term survival for the patient. By decreasing the amount of manipulation of the structures surrounding the tumor, morbidity such as swallowing difficulties, involvement of speech mechanisms, and other cranial nerve palsies is greatly decreased. The mortality for the operation should certainly be less than 2 percent; it depends greatly on the quality of the team as a whole, including the neuroanesthesiologist and the intensive care specialist.

It has been the policy to repeat the CT scan as soon as feasible and certainly before initiating further therapy. Because of the report of a large number of unsuspected spinal cord metastases, myelography has also been performed prior to further therapeutic measures, although few positive studies have been found.

After surgery, early mobilization is encouraged, and the steroid dosage is decreased over the course of 2 weeks. The patient is watched carefully for sterile meningitis. When it occurs, an increase in steroid dosage usually produces dramatic improvement in the symptoms.



Adjunctive Therapy and Complications


Since the time of Cushing, it has been clearly demonstrated that the most important single therapeutic procedure after surgery for removal of a medulloblastoma is radiation therapy. The commonly accepted radiotherapeutic regimen for the management of medulloblastoma is 5000 to 5500 rad to the posterior fossa, 4000 to 4500 rad to the whole cranial cavity, and 3000 to 3500 rad to the spinal axis. This program is usually started within 3 weeks of surgical removal and is spread over a course of 6 to 7 weeks. The radiation should be carefully collimated, and it is of utmost importance that there be adequate overlap of the fields. In many instances of patients referred because of recurrence of metastatic medulloblastoma, review of the earlier radiation therapy fields has shown that metastasis occurred in gaps between the fields.

The major problem resulting from this regimen is the inability of the young, developing brain to tolerate these large amounts of radiation therapy. Because of this, radiation therapy in the child under the age of 2 is avoided and chemotherapy used instead. Nevertheless, it should be pointed out that the prognosis in the very young child with medulloblastoma is far more pessimistic than in the child over the age of 2, with few of the younger children surviving.

A chemotherapeutic trial of vincristine and lomustine (CCNU), vincristine 1.5 mg/m2 for eight injections during the postoperative period and the other treated concurrently with radiation therapy. Four weeks after completion of the radiation therapy, vincristine was reinstituted at the same dosage, as well as CCNU, 100 mg/m2 by mouth, and prednisone, 40 mg/m2 by mouth, in three divided doses for 14 days. During this l4-day cycle, vincristine is given on days 1, 8, and 15. The cycle is repeated every 6 weeks for a total of eight cycles over a period of 1 year. There is a beneficial effect of chemotherapy, long-term results have shown little statistical difference between the treated and untreated children, with a slightly improved outcome in those treated with chemotherapy. However, further improvements in survival rate can be obtained by aggressive surgical resection followed closely by both radiation therapy and chemotherapy in the form of 8 cycles of CCNU, vincristine, and cis­platin.



Results of Therapy


The 5-year survival for this tumor has been reported to vary between 25 and 70 percent. In a hospital specializing in the treatment of children with cancer, a 5-year survival rate of 60 percent or more can be expected following total excision and radiation treatment in patients over the age of 2. In younger patients, an almost 100 percent mortality can be expected within 2 to 3 years. Several attempts have been made to analyze the results of treatment of medulloblastoma. The concept of a period of risk is important. It has been postulated that for tumors of congenital origin, particularly Wilms' tumor, the period of risk encompasses a time equal to the age of the patient at diagnosis plus 9 months (Collins' law). However, in recent years, with prolonged survival of patients with medulloblastoma and with better record keeping, numerous exceptions to this law have been found, with medulloblastoma recurring after a period far exceeding the predicted term of risk, in some cases by as much as 10 years.

Finally, in discussing the prognosis of this tumor, the complications of combined therapy should be mentioned. Growth hormone deficiency has been reported in as many as 80 percent of the children so treated, and neuropsychological disorders, particularly in performance and short-term memory function, can usually be shown.

Please refer to case-1 and case-2 for demonstration.
 


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