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Katia Nogueira, MD 1
Bernardo Liberman, MD, PhD 1
Luis Roberto Salgado, MD, PhD 1
Maria Elizabeth Rossi Silva, MD, PhD 1
Jose Augusto Buratini, MD 2
Arthur Cukiert, MD, PhD 2
Departments of Endocrinology (1) and Neurosurgery (2) Hospital Brigadeiro, São Paulo SP, Brazil
Dr. Arthur Cukiert
Director - Neurosurgery, Hospital Brigadeiro
R Dr Alceu de Campos Rodrigues 247, 12 andar, cj 121
São Paulo SP , Brazil
Precocious Puberty (PP) can be caused by inhibitory or stimulatory factors involving the hypothalamic-pituitary axis. Lesions causing PP are often located at the posterior hypothalamic or pineal region.
Pineal region tumors are generally divided into germ cell tumors (germinomas, teratomas, endodermal-sinus tumors, embryonal carcinomas and choriocarcinomas), pineal parenchymal tumors (pineocytomas, pineoblastomas, gangliomas, gliomas, astrocytomas, ependymomas), tumors arising from adjacent structures (meningiomas, hemangiopericytomas) and pineal cysts. The secretion of tumor markers (9) can also differentiate pineal tumors and indicates the presence of nongerminomatous germ cell tumors (8).
Pineal tumors are rare, making up from 0,4 to 1 % of all intracranial tumors. In the pediatric age group they account for 3 to 8 % of brain tumors (1). Germ cell tumors are the most common at the in pineal region. Germinomas account for 65% of the patients; teratomas, embryonal carcinomas, endodermal-sinus tumors and choriocarcinomas account for 26 % and 9 % of the patients have a mixed histology (6).
Heubner made the first report of PP associated to a pineal tumor in 1898 in a patient with teratoma (4). The PP caused by pineal disease is due to the pressure or destructive effects by the tumor on the hypothalamic function or by ectopic beta human chorionic gonadothrophin (b -hCG) secretion by the tumor.
Primary intracranial choriocarcinoma is an extremely rare tumor. It is thought to develop within a teratoma and it occurs predominantly in the pineal region or the posterior portion of the third ventricle (7). It is seen predominantly in males during the first 2 decades of life (3) and it can secrete b -hCG.
This study reports an 8 years-old boy with PP associated to pineal immature teratoma with areas of choriocarcinoma.
ALO, a 7 years-old boy had been well until 2 years before admission when he developed precocious puberty. There was enlargement of the penis, appearance of pubic hair, weight gain, linear growth and increased aggressiveness. His height and weight were above the 75 percentile. His axillary and pubic hair, penile length and testicular size were compatible with a Tanner II - III stage. Neurological examination was normal. The radiographic bone age was 11 years.
Magnetic resonance (MR) imaging of the brain has shown a 3,0 cm mass in the pineal region. There were multicystic and heterogeneous contrast-enhancing solid areas. There was no hypertensive hydrocephalus. There was compression of the posterior mesencephalon.
Cerebrospinal fluid (CSF) and plasma beta human chorionic gonadothrophin (b -hCG) levels were elevated. Plasma testosterone was elevated. A LHRH infusion test has shown a blunted prepubertal response.
He was first submitted to a radiotherapy trial, which consisted in the fractionated delivery of 2500 rads. After two weeks, MR documented an actual increase in the tumor volume. No decrease in beta-hCG or testosterone levels in the serum was noted.
The tumor was exposed through a subocciptal supracerebellar infratentorial approach with the patient in the sitting position. A total macroscopic resection of the pineal mass was obtained. He had an uneventful postoperative recovery, except for a transient (5 days) Parinaud's syndrome. MR obtained 2 weeks after surgery showed no residual lesion. A decrease (but no normalization) of the plasma b -hCG levels was noted. Pathological examination revealed an immature teratoma with extensive areas of choriocarcinoma. One month after surgery he developed acute hydrocephalus, requiring a ventriculo-peritoneal shunt. Beta-hCG and testosterone levels remained high and chemotherapy with vepezide and carboplastine was started after shunting. Plasma b -hCG and testosterone levels normalized, increasing again one month after the end of chemotherapy. Stereotactic radiotherapy was performed with a total dose of 3000 rads (not including the 2500 rads administered previously). Three months after stereotactic radiotherapy MR showed hemorrhage (not present 2 weeks after surgery) in the pineal region. The patient remained asymptomatic. Serum testosterone and beta-hCG increased again. A new chemotherapy regimen was started with Topotecan, without any noticeable result.
He developed Parinaud's syndrome 6 months after stereotactic radiotherapy. CT and MR showed hemorrhage and edema around the hematoma. There was a right thalamic area of radionecrosis and an extensive area of demielinization over the mesencephalic and thalamic regions. Neurological status improved after high-dose corticotherapy.
Pineal teratomas are extremely rare lesions and infrequently cause PP. Nevertheless, endocrine abnormalities have been reported associated to pineal tumors, being PP the most common (19). PP can be seen with choriocarcinoma located in this region (9). Hypothalamic lesions have been associated to sexual precocity more frequently than pineal gland lesions (4).
Although a century has elapsed since Heubner first described PP associated to pineal teratoma, the pathophysiology of this association remains poorly understood. Kitay (11) suggested that PP be caused by destruction of the normal pineal parenchymal tissue by tumors, resulting in the decrease of secretion of a pineal antigonadothrophic substance. The destruction of hypothalamic inhibitory centers by the expansion of a tumor, causing increased gonadothrophin secretion and consequently PP, have also been considered as a possible physiopathological factor (4). Cohen (4) and Sklar (17) reported patients in whom the surgical removal of the tumor was followed by a decrease of the levels of b -hCG which led to the cure of PP, suggesting that the high levels of this hormone were responsible for it .
The beta-subunit of hCG and LH are identical and b -hCG would have a LH-like action. Follicular development and estrogen production are dependent on the presence of LH and FSH. On the other hand, LH alone is capable of stimulating Leydig’s cells to produce testosterone (17). Tumors that secrete b -hCG produce PP in boys but rarely in girls (4,17). Nonetheless, Kitanaka (10) reported a 6 years-old girl with PP and hCG-secreting suprasellar immature teratoma. Serum estrogen was elevated and a LHRH infusion test showed a prepubertal response. Beta-hCG would also disclose a weak FSH-like activity, which could play a role in the development of PP in girls. The presence of intracranial germ cell tumors with high levels of b -hCG secretion would also be needed for the development of PP in girls. The rarity of such tumors is possibly related to the low prevalence of PP in girls (10). We have found 17 patients with pineal tumors associated to PP reported in the literature (2,13,16,18)(Table I). All were boys with high levels of serum b -hCG.
Serum and CSF markers have allowed the identification of pineal tumors. Choriocarcinoma yields a marked increase in serum and CSF b -hCG levels; endodermal-sinus tumors are associated with increased levels of alpha-fetoprotein (AFP) and embryonal carcinomas can produce increased levels of both b -hCG and AFP (3,9). High levels of b -hCG in CSF, serum and urine in the absence of AFP are virtually pathognomonic of choriocarcinoma (5,12). Mature teratomas and germinomas without malignant germ cell elements do not secrete either b -hCG or AFP (8,12). Nongerminomatous germ cell tumors are an invariably fatal subgroup within the pineal germ cell tumors. There is no effective therapeutic regimen (1).
Pineal immature teratomas represent a challenge from the surgical and oncological points of view. Stereotactic or open biopsy may help in guiding the therapeutic approach (9). Histological diagnosis is necessary before radiotherapy (RT) or chemotherapy in most of the patients with intracranial tumors. Nevertheless, a primary radiotherapy trial can be used preoperatively in patients with pineal or suprasellar tumors strongly suggestive of germinoma, such as in our patient. Hoffman (9) showed a decreasing operative mortality and morbidity, having been null in the most recent patients. He suggested that surgery for pineal tumors can be recommended, being safe and indicated in benign tumors, which did not respond to RT. However, there is evidence that RT for malignant pineal tumors is more effective after radical tumor removal (9). Chan (3) reported that in 35 patients with intracranial choriocarcinomas (9 pineal tumors) there was no cure in those patients who were treated either with surgery or RT alone or in combination.
Rich (14) studied the treatment results of 25 patients with pineal and suprasellar germ cell tumors. Germinoma responded favorably to RT, whereas solitary pineal tumors and teratomas with marker’s positivity have not. The association of CHEMOTHERAPY with multiple drugs has been related to improved survival in patients with nongerminomatous germ cell tumors (20). Hermann (8) and Robertson (15) advocated the use of chemotherapy associated to the surgical removal and RT, suggesting that survival rates up to 74 % in 5 years could be achieved.
Our patient presented PP with increased serum and CSF levels of b -hCG. There was a prepubertal response in the LHRH infusion test, compatible with PP due to increased levels of b -hCG. After the initial RT trial there was an increase of the tumor’s size, which can occur in teratomas. He had high levels of b -hCG in the absence of AFP, biochemical features compatible with the histological diagnosis of choriocarcinoma, associated or not to a germinomatous component.
Hydrocephalus due to obstruction of the aqueduct or posterior third ventricle and Parinaud’s syndrome are common findings in patients with space occupying lesions in the pineal region. Both were noted during the clinical course of our patient. Beta-hCG levels did not decrease even after radical surgical removal, RT and chemotherapy. This is compatible with a highly malignant choriocarcinoma component within the teratoma.
In spite of an aggressive therapeutic approach, germ cell lesions with a choriocarcinoma component still bear a bad clinical prognosis.
Pineal Teratomas with Precocious Puberty
Author, Year, (Reference) N Sex Histology b -HCG
Romshe, 1975, (16) 1 M non-available high
Sklar, 1981 , (17) 1 M non-available high
Chan, 1984, (3) 9 M choriocarcinoma high
Blumel, 1985, (2) 1 M choriocarcinoma high
Uede, 1986, (18) 1 M teratoma high
Cohen, 1991, (4) 1 M immature teratoma high
Hoffman, 1994,(9) 2 M choriocarcinoma high
Noshita, 1997, (13) 1 M teratoma high
Nogueira, 2000 1 M immature teratoma high
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