Case report and review of the literature
Katia Nogueira, MD 1,
Bernardo Liberman, MD, PhD 1,
Luis Roberto Salgado, MD, PhD 1,
Maria Elizabeth Rossi Silva, MD, PhD 1,
José 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
1. Abay E, Laws ER, Grado GL, Brackman JE, Forbes GS, Gomez MR, Scott M (1981) Pineal tumors in children and adolescents. Treatment by CSF shunting and radiotherapy. J Neurosurg 55:889-895.
2. Blumel P, Grumayer ER, Machacek E, Stogmann W (1985) Beta-HCG producing choriocarcinoma of the pineal area as a cause of precocious puberty. Helv Paediatr Acta 40:473-9.
3. Chan HSL, Humphreys RP, Hendrick EB, Chuang SH, Fitz CR, Becker LE (1984) Primary intracranial choriocarcinoma: A report of two cases and a review of the literature. Neurosurgery 15:540-45.
4. Cohen AR, Wilson JA, Sadeghi-Nejad A (1991) Gonadothrophin-secreting pineal teratoma causing precocious puberty. Neurosurgery 28:597-603.
5. Dehner LP (1983). Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14:493-511.
6. Felix I, Becker LE (1991) Intracranial germ cell tumors in children: an immunohistochemical and electron microscopic study. Pediatric Neurosci 16:541-51.
7. Giuffrè R, Di Lorenzo N (1975). Evolution of a primary intrasellar germinomatous teratoma into a choriocarcinoma. J Neurosurg 42:602-604.
8. Herman HD, Westphal M, Winkler K, Laas RW, Schulte FJ (1994) Treatment of nongerminomatous germ-cell tumors of the pineal region. Neurosurgery 34:524-529.
9. Hoffman HJ, Yoshida M, Becker LE, Hendrick EB, Humphreys RP (1994) Pineal region tumors in childhood- experience at the Hospital for Sick Children. Pediatric Neurosurgery 21:91-104 .
10. Kitanaka C, Matsutani M, Sora S, Kitanaka S, Tanae A, Hibi I (1994) Precocious puberty in a girl with an hCG-secreting suprasellar immature teratoma. Case report. J Neurosurgery 81:601-4.
11. Kitay JI (1954) Pineal lesions and precocious puberty: A review. J Clin Endocrinol 14:622-625.
12. Kurman RJ, Scardino PT, McIntire KR, Waldmann TA, Javadpour N, Norris HJ (1978) Cellular localization of AFP and HCG in germ cell tumors of the testis and ovary. Scand J Immunol 8:127-130.
13. Noshita N, Shirane R, Yoshimoto T, Onuma T (1997) A case of pineal teratoma arising from hydrocephalus of unknown cause. No Shinkei Geka 25:549-53.
14. Rich TA, Cassady JR, Strand RD, Winston KR (1985) Radiation therapy for pineal and suprasellar germ cell tumors. Cancer 55:932-40.
15. Robertson PL, DaRosso RC, Allen JC (1997) Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32:71-80.
16. Romshe CA, Sotos JF (1975) Intracranial human chorionic gonadotropin-secreting tumor with precocious puberty. J Pediatrics 86:250-252.
17. Sklar CA, Conte FA, Kaplan SL, Grumbach MM 1981) Human chorionic gonadotrophin-secreting pineal tumor: Relation to pathogenesis and sex limitation of sexual precocity. J Clin Endocrinol Metab 53:656-660.
18. Uede T, Takaya S, Shinya T, Tanabe S, Hashi K, Sohma T (1986) A case of pineal teratoma with intraventricular free fat seen in CT scan. No Shinkei Geka 14:1577-82.
19. Wass JAH, Jones AE, Rees LH, Besser GM (1982) Beta-hCG producing pineal choriocarcinoma. Clinical Endocrinology 17:423-431.
20. Wolden SL, Wara WM, Larson DA, Prados MD, Edwards MS, Sneed PK (1995) Radiation therapy for primary intracranial germ cell tumors. Int J Radiat Oncol Biol Phys 32:943-9.
Fernando Pimentel, Bernardo Liberman, Arthur Cukiert, Jayme Goldman, Luis Roberto Salgado
The use of glucocorticoid (GC) during and after surgery has been recommended in patients presenting with cortisol deficiency before surgery or in those with chronic hypercortisolism (p.e, cortical adrenal tumor) in whom surgery may cause abrupt onset of adrenal insufficiency. It has been a common clinical practice to use intravenous hydrocortisone (HC) during transesphenoidal surgery (TS) for Cushing’s disease (Tyrrell 78, Fitzgerald 82). GC administration should be based on the magnitude of the stress and the known GC production rate associated with it. However, there have been no studies addressing the GC needs during TS. The GC regimens commonly used during TS have been empirically defined or based on stress data obtained from other types of surgical procedures and vary from 200 to 400 mg of HC during the day of surgery (Williams, Arafah, Tyrrell 78, Fitzgerald 82). In the present study we assessed the need for GC replacement therapy during TS in patients with sellar tumors.
SUBJECTS AND METHODS
Thirty-two patients with sellar tumors were evaluated before and after TS. Sellar tumors were detected by MRI in all patients. Suggestive tumor tissue was visualized and resected by the neurosurgeon during surgery and histological examination and immunohystochemistry confirmed the diagnosis in all patients. Another 6 patients submitted to bilateral adrenalectomy for the treatment of Cushing’s disease were included in order to study the influences of exogenous GC administration on the rate of free cortisol urinary (UFC) excretion in patients without endogenous cortisol production. Informed consent was obtained from patients and the research protocol was approved by the Institutional Review Board.
In 12 patients (group I: age = 36.2 ( 2.2 years; 3 men and 9 women; BMI = 28.6 ( 0.7 kg/m2) no GC was administered during surgery or in the postoperative days. This group included 6 patients with non-secreting adenoma, 5 with acromegaly and one with prolactinoma. All patients had normal cortisol secretion before and after surgery as determined by a serum cortisol peak greater than 18 (g/dL during an insulin tolerance test (ITT) (0.1 – 0.3 U insulin / Kg IV).
Twelve patients (group II: age = 29.6 ( 3.3 years; 6 men and 6 women; BMI = 29.0 ( 1.6 kg/m2) received GC trans- and post-operatively. This group included 10 patients with Cushing’s disease, one with acromegaly and one with craniopharyngioma. They received 400 mg of intravenous HC during the day of surgery (PO-i) (100 mg before and at the end of surgery, and 100 mg b.i.d ) and 200 mg during the first post-operative day (PO-1) (50 mg q.i.d). Eight patients (group III: age = 36.4 ( 4,1 years; 2 men and 6 women; BMI = 26.2 ( 1.2 kg/m2) received a lower dosage of GC during the day of surgery and in the post-operative days. This group included 5 patients with Cushing’s disease, 1 with acromegaly and 2 with non-secreting adenoma. They received 200 mg of intravenous HC during the day of surgery (PO-i) (50 mg before and at the end of surgery, and 50 mg b.i.d) and 100mg of HC during PO-1 (50 mg b.i.d). Groups II and III patients without Cushing’s disease that received GC disclosed a low cortisol reserve during ITT (cortisol peak lower than 18 (g/dL) in a preoperative evaluation. Whole day urinary samples were collected for UFC determination during PO-i and PO-1 from all patients. Six patients (Group IV: age = 40.8 ( 3.0 years; 2 men and 4 women; BMI = 29.1 ( 4.8 kg/m2) that were submitted to bilateral adrenalectomy for treatment of Cushing’s disease received exogenous GC as follows: 400 mg/day of intravenous HC on the first day (PI-i) (100 mg q.i.d) and 200 mg/day on the second day (PI-1) (50 mg q.i.d)), thus resulting in a GC schedule similar to that of group II patients. UFC excretion rate was measured during PI-i and PI-1 in all patients.
Signs and symptoms of peripheral cortisol deprivation were evaluated by means of sequential recording of symptoms and measurements of body weight, body temperature, blood pressure and heart rate. Blood electrolytes, glucose, BUN, creatinine and white and red blood cell analysis were carried out in all patients before and after surgery.
UFC was measured by a radioimmunoassay (RIA) kit after extraction with dichloromethane (Diagnostic Products Corp., Los Angeles, CA). The normal range was 20 to 90 (g/24 hours and inter- and intra-assay variation’s coefficients were 6.9% and 6.0%, respectively.
Data were analyzed by Kruskal-Wallis one way analysis of variance (ANOVA) and the results were reported as mean ( SE. P-Values below 0.05 were considered statistically significant.
No statistical difference was observed in age and body mass index (BMI) between the studied groups.
UFC excretion decrease from PO-i / PI-i through PO-1 / PI-1 in all patients. UFC excretion during PO-i in group II patients (9350 ( 1631 (g/24h) was approximately 14 times greater than that seen in group I patients (679 ( 134 (g/24h) (p<0,05) and 5 times greater than that in group III subjects (1849 ( 298 (g/24h) (p<0,05). Mean UFC during PO-1 observed in group II patients (3233 ( 334 (g/24h) was also approximately 15 times greater than that of patients in group I (217 ( 37 (g/24h) and 4 times greater than that of group III subjects (755 ( 126 (g/24h). No statistical difference was observed between groups I and III. There was no difference between the mean UFC excretion in groups II and IV patients (9350 ( 1631 (g/24h and 10120 ( 1613 (g/24h, respectively) during PO-i / PI-i or PO-1 / PI-1 (3233 ( 334 (g/24h and 3891 ( 782 (g/24h, respectively).
Signs and symptoms of peripheral cortisol deprivation were not observed in any patient during PO-i or PO-1. Eight patients from Group II and 6 patients from group III showed clinical and laboratorial evidence of adrenocortical insufficiency by the third post-operative day (6 patients from group II and 3 from group III had Cushing’s disease). In group II, 2 patients with Cushing’s disease presented transitory diabetes insipidus. No other surgical complication was observed in this series.
A significant increase in blood pressure was observed in all patients during PO-i. This was mainly seen in the first two hours after the end of surgery, but the mean blood pressure measurements obtained in group I during PO-i were not different from those obtained in groups II and III. No difference was observed among groups in serum sodium, potassium and creatinine concentrations.
Adrenal insufficiency after TS is rare but often fatal if not diagnosed and treated (Harris 90 ). Patients who might be at risk to develop post-operative adrenal axis faillure are usually treated empirically with different GC schedules. Sub-physiologic replacement of GC may result in hemodynamic abnormalities such as drop in blood pressure, systemic vascular resistance, left ventricular stroke work index and absent tachycardic response (Udelsman 86 and ref. 9 – Mohler and 10 – Alford do Harris 90). GC excess is associated with well known immunosuppression and increased susceptibility to infection, electrolyte unbalance, reduced carbohydrate tolerance, hypertension and catabolic effects on muscle and wound healing (ref 7-13 do Udelsman, Baxter 90, Ref 9 do Lamberts97, Salem 94). We and others (Arafah, ) used a large dose of GC during and after TS until recently. Data from the present study demonstrated that a dose of 400 mg of HC during the peri-operative day yielded an UFC excretion rate considerably greater (14 times) than that observed in patients who underwent the same surgical stress but did not receive GC replacement. During PO-1 UFC excretion was also greater (15 times) in patients who received HC intravenously than in those who did not. When a lower dose of HC (200 mg/day) was administered during the day of surgery (group III) the mean UFC excretion remained greater (3 times) than that of patients who did not receive HC (Group I), although statistical difference was not achieved.
Several different parenteral GC replacement schedules have been published in order to study the cortisol secretion rate during or immediately after surgery (ver ref. do Kehlet – página 261). Some studies suggested that physiologic cortisol supplementation may be sufficient for patients submitted to major surgical procedures (ref. 14 a 16 do Udelsman 85, ref 30 e 31 do Czerwiec 96). Udelsman et al (1985) demonstrated that in adrenalectomized primates submitted to cholecystectomy the mortality rate in the sub-physiologically GC-treated group was higher than in the controls or in the group receiving full GC replacement. There was no difference between animals receiving full or supra-physiologic GC replacement.
Less than 1% of the excreted cortisol is eliminated as urinary free cortisol (Williams, ). In adults, the adrenal glands produce 75 to 150 mg of HC during the first 24 hours after major surgery (Kehlet 73, ref. 32, 39, 105, 57, 106 e 108 do Salem 94, ver ref doLamberts 97 e outras) and the UFC excretion rate should be approximatly 750 to 1,500 (g / day during this period (about 10 times the normal values in non-stressful situations). Our data are in accordance with this estimate: group I patients mean UFC excretion was 679 (g/24h (range: 185 to 1750 (g/24h) during PO-i. Theorectically, after administration of 200-500 mg of HC, UFC excretion should range from 2,000 to 5,000 (g in 24 hours (1% of the administered HC). Patients in the present study who received 200 mg during PO-i Group III) showed UFC excretion rates which corresponded to that value. However, in subjects receiving 400 mg of HC this percentage was approximately 2%. This increased cortisol excretion rate might be due to the fact that urinary excretion of free cortisol increases when serum cortisol concentration exceeds cortisol binding globulin (CBG) capacity (25g/dL) (Williams, Greenspan 321; Bright 95). This occurs more frequently after bolus injections. Actually, we also observed a great inter-individual variability in UFC excretion as noted previously by others. This may be due to differences in CBG concentration, sex, age and BMI (Bright 95, Barton 93; Lamb 94). We did not observe statistical differences in age and BMI in this series.
Our data strongly suggest that intravenous HC doses of 200 mg during PO-i and 100 mg during PO-1 might be enough to prevent adrenal insufficiency in patients at risk after TS. Kehlet et al. ( ) suggested injecting 25 mg intravenous HC every 4 hours. They also suggested a schedule for continuous infusion consisting of a 100 mg / day regimen until gastrointestinal function allows oral intake of usual GC replacement therapy. Although Czerwiec et al ( 1996 ) had recommended an intravenous HC dosage of 300-400 mg/day for patients undergoing major stress, others (Lamberts 97 e Salem 94) suggested a 25mg/day regimen for minor stress, 50-75 mg/day for moderate stress and 100-150 mg/day for major stress.
We and others (JCEM 97) have observed that ACTH secretion in patients with Cushing’s disease may persist during some post-operative days after total tumor resection, and that prophylactic GC administration during this period might not be necessary for these patients. Thorner et al. (abstr. 97) demonstrated that serum cortisol was still elevated 6 hours after surgery in a great number of patients (12 of 17 patients) who had achieved remission after transsphenoidal surgery for Cushing’s disease and did not receive GC during the procedure. A rapid decrease in blood cortisol levels by 24 to 48 hours after surgery was observed in the same patients studied by the same authors. This endogenous production of cortisol could raise the mean UFC excretion in patients with Cushing’s disease receiving exogenous GC as in group II and III. We have observed no difference between mean UFC excretion during PO-i / PI-i in groups II and IV. These findings suggest that endogenous production of cortisol might play only a small role in determining the rates of post-operative UFC excretion. Moreover, we observed that UFC values from patients with ACTH-secreting pituitary tumors or other sellar tumors in groups II and III were similar during PO-i and PO-1 (Figure 1).
The side effects of high-dose GC administration were also analysed in this study. However, only a few of these effects could be analyzed because there were important differences in the clinical spectrum of the groups. The hyperglycemic effect of GC has been known for a long time (ref 8 and 9 do Wayne 77; ref. Kitabchi do Bowes 91, Malerbi 88, ref – Al-Shoumer do Peacey 97), but we were unable to compare fasting glucose values in group I with groups II and III since there were much more diabetic patients in the latter groups than in the former . The hypertensive effect of GC could not be evaluated because there was a marked increase in blood pressure during PO-i (more significant in the first 2 hours after surgery) in all patients. This immediate post-operative hypertensive effect has been previously described in other surgical procedures and is related to surgical stress (Udelsman 87). No electrolyte unbalance, gastric ulceration or psychiatric disorder was observed in any patient.
Many of the published GC regimens probably represent supra-physiologic steroid replacement therapy. Data obtained in this study strongly suggest that group III regimen (200 mg / day during PO-i and 100 mg / day during PO-1) is probably the best one for patients being submitted to TS for the treatment of sellar tumors.
Correlação da ressonância magnética, bioquímica e de achados intra-operatórios de tumores císticos da região selar
Najla Z. Halabi-Almeida; Fernando R. Pimentel-Filho; Márcia Nery; Luiz R. Salgado; Jayme Goldman; Bernardo Liberman; Arthur Cukiert.
Serviços de Endocrinologia e Neurocirurgia do Hospital Brigadeiro-São Paulo
A ressonância magnética (RNM) tem sido utilizada, cada vez mais, no diagnóstico de patologias da região selar e supraselar. Em especial, há necessidade de um diagnóstico pré-operatório mais preciso da natureza dessas lesões. Tanto tumores pituitários quanto craniofaringiomas podem apresentar componentes sólidos e císticos. Este componente cístico pode ser iso-, hipo- ou hiperintenso em relação ao parênquima cerebral.
A hiperintensidade de imagem do fluido cístico de craniofaringiomas, em T1, na RNM vem sendo atribuída a presença de proteínas, hemoglobina, colesterol ou a combinação desses materiais (1,2), enquanto que a hiperintensidade nos adenomas apopléticos tem sido relacionada ao sangramento local.
Um estudo sistemático do conteúdo desses cistos tumorais ainda não foi obtido, permanecendo a dúvida em relação à hiperintensidade de sinal na RNM. A dificuldade de obter o conteúdo desses cistos, antes do mesmo de ser contaminado pelo procedimento cirúrgico, parece ser a razão principal para a escassez desse tipo de estudos.
Pusey e colaboradores (3) correlacionaram a hiperintensidade de sinal em T1 na RNM com o conteúdo elevado de colesterol e presença de metahemoglobina em craniofaringiomas.
O presente estudo relaciona as características de intensidade de sinal na RNM com a análise bioquímica quantitativa do líquido tumoral e achado cirúrgico intra-operatório.
PACIENTES E MÉTODOS
Sete pacientes com tumores intraselares císticos, com idade variando entre 8 e 34 anos, foram estudados. Os pacientes foram divididos em 2 grupos: Grupo I, pacientes com adenomas apopléticos (hemorragias intratumorais assintomáticas)(n=3; duas mulheres e um homem); Grupo II, pacientes portadores de craniofaringioma (n=4; dois homens e duas mulheres).
Todos os pacientes foram submetidos à cirurgia, transesfenoidal ou transcraniana, e os cistos foram aspirados previamente à ressecção tumoral. O líquido intratumoral foi submetido a análise bioquímica com dosagem de proteínas totais e frações, colesterol e triglicérides.
As imagens da RNM em T1, obtidas em aparelho 1.5T de alta resolução foram classificadas de acordo com a intensidade de sinal em relação ao parênquima cerebral e correlacionadas com achados intraoperatórios.
A tabela I mostra a análise quantitativa bioquímica do líquido tumoral de cada paciente, assim como a intensidade de sinal na RNM e a presença ou não de cristais e grumos de colesterol à cirurgia. Nos 3 pacientes portadores de macroadenoma, a média de colesterol e proteínas do líquido tumoral foi de 146,6 mg/dl e de7,1 g/dl, respectivamente. Nos 4 pacientes com craniofaringiomas, encontramos média de colesterol e proteínas intracística de 161 mg/dl e de 5,2 g/dl, respectivamente. Os 2 pacientes com hipersinal na RNM (Figura 1), em T1, apresentavam cristais ou grumos de colesterol grosseiros à macroscopia no intraoperatório.
Os adenomas onde houve necrose intratumoral e cavitação cística apresentavam intensidade de sinal na RNM variável, compatível com o provável tempo de sangramento local, como sugerido pelo aspecto mais seroso ou hemorrágico do líquido obtido. Os hipointensos apresentavam líquido intra-tumoral seroso (amarelo-citrino) e os hiperintensos possuíam composição hemorrágica à ectoscopia cirúrgica. Como tratavam-se de pacientes com apoplexia subclínica, não houve maneira de estimar a data do episódio hemorrágico.
A presença de hipersinal na RNM em T1 nos tumores da região selar vem sendo atribuída à presença de colesterol, proteínas ou hemoglobina intra-cisto. Sartoretti-Schefer e colaboradores (4), estudando pacientes portadores de craniofaringiomas, sugeriram que os cistos da região selar contêm quantidade variável de colesterol, triglicérides, metahemoglobina, hemoglobina e células epiteliais e que o sinal de intensidade destes cistos é influenciado principalmente pela concentração de proteínas maior ou igual a 90 g/L e à presença de metahemoglobina livre. Segundo estes autores, a concentração de colesterol e triglicérides não parece mudar a intensidade de sinal, pois nenhuma alteração pôde ser observada com concentrações lipídicas diferentes intracisto.
Vion-Dury e colaboradores (5) propõem que a variabilidade de sinal de cistos epidermóides é causada pelo valor de tempo de relaxamento diferente correspondendo a diferentes concentrações de queratina, colesterol e água.
Volker e colaboradores (6) estudaram a correlação de cistos de Rathke com a imagem encontrada na RNM em 19 pacientes e relataram que as mesmas são muito variáveis. Sete de 19 imagens císticas tinham semelhança com o líquor, duas eram iso- a hipointensas, enquanto 10 casos apresentavam imagens iso- a hiperintensas em T1. Em 4 pacientes desse último grupo foram encontrados cristais de colesterol no fluido cístico, o que explicou a hiperintensidade de imagem obtida. Outros autores têm sugerido que a presença de mucopolissacárides no cisto é responsável pelo aumento de intensidade em T1 na RNM (7).
Scotti e colaboradores (8) discutem a aparência na RNM de cistos colóides do terceiro ventrículo e sugerem que o sinal hiperintenso dentro do cisto é devido a substrato mucóide.
Ahmadi e colaboradores (9) também obtiveram dados que sugeriram que nível de proteína maior ou igual a 90 g/dl, a presença de metahemoglobina livre ou ambos podem aumentar a intensidade de sinal do fluido cístico de craniofaringiomas na imagem em T1 na RNM e que colesterol e triglicérides não elevam intensidade de sinal do líquido intra-cisto. Em nosso estudo, os níveis de proteína não se relacionaram ao sinal na RNM; nossos dados sugerem um papel isolado dos níveis de metahemoglobina na alteração de sinal de adenomas apopléticos.
Verificamos que as apoplexias nos adenomas hipofisários apresentam hiperintensidade de sinal compatível com o tempo de sangramento intratumoral como definido pela macroscopia do líquido intracístico durante o ato cirúrgico. Assim, imagens hipointensas na RNM em T1 apresentam líquido intra-cisto seroso ( amarelo-citrino ) e os hiperintensos têm composição hemorrágica à ectoscopia cirúrgica. A concentração de metahemoglobina nos cistos de craniofaringiomas é irrelevante, já que não há sangramento espontâneo intracístico nestes casos.
Em nossos pacientes portadores de craniofaringiomas, o hipersinal na RNM em T1 não se correlacionou com a quantidade de colesterol e proteínas intracisto, porém houve correlação da imagem hiperintensa com a presença, devidamente documentada por vídeo, de cristais de colesterol grosseiros e grumos de colesterol à ectoscopia cirúrgica.
O presente estudo sugere que os adenomas pituitários apopléticos apresentam intensidade de sinal de acordo com o tempo de sangramento local. Nos craniofaringiomas, a hiperintensidade relacionou-se exclusivamente com a presença de cristais ou grumos de colesterol achados à ectoscopia cirúrgica e não às concentrações de proteínas e lípides. As razões para as discrepâncias no que diz respeito às concentrações de proteínas e lípides no sinal da RNM neste e nos outros raros estudos que discutem o assunto não são claras. No entanto, os estudos já publicados não discutem o papel dos cristais e grumos de colesterol, que parecem representar o fator isolado mais importante como determinante do sinal na RNM.
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Tabela I – Resumo clínico da série.
Figura 1 – Imagens císticas em tumores da região selar. A: Corte coronal de RMN em T1 mostrando macroadenoma cístico, provavelmente decorrente de sangramento remoto (Caso III); B: Corte sagital de RMN em T1 mostrando macroadenoma com sangramento mais recente (Caso I); C: Corte coronal de RMN em T1, mostrando craniofaringioma com grande cisto hiperintenso (Caso IV); D: Corte sagital de RMN em T1 mostrando craniofaringioma cístico. A maior parte do cisto era hipointensa, no entanto, nota-se depósito hiperintenso na base da sela que correspondia a grumos de colesterol à cirurgia.
CORRELAÇÃO DA RESSONÂNCIA MAGNÉTICA, BIOQUÍMICA E DE ACHADOS INTRA- OPERATÓRIOS DE TUMORES CÍSTICOS DA REGIÃO SELAR.
Najla Z. Halabi-Almeida; Fernando R. Pimentel-Filho; Márcia Nery; Luiz R. Salgado; Jayme Goldman; Bernardo Liberman; Arthur Cukiert.
Serviços de Endocrinologia e Neurocirurgia do Hospital Brigadeiro-São Paulo
Os tumores da região selar frequentemente possuem componentes sólidos e císticos. O conteúdo cístico dos mesmos pode sugerir o diagnóstico anátomo-patológico. A hiperintensidade de sinal na RNM, em T1, destes cistos tem sido atribuída à alta concentração de proteínas, lípides ou derivados da degradação da hemoglobina. Sete pacientes com tumores císticos da região selar (3 macroadenomas, 4 craniofaringiomas) e que possuíam RNM de alta resolução preoperatória foram estudados. Todos foram operados por via transesfenoidal ou transcraniana e em todos os casos o líquido do cisto foi aspirado antes do início da retirada do tumor e teve sua concentração protêica e lipídica analisada. As médias das concentrações de proteínas e lípides nos cistos dos macroadenomas foram de 7,1 g/dl e de 146,6 mg/dl, respectivamente; já nos cistos dos craniofaringiomas, estas médias foram de 5,2 g/dl e de 161 mg/dl, respectivamente. Nos macroadenomas, a intensidade de sinal relacionou-se ao tempo do sangramento intratumoral como sugerido pelo aspecto do líquido intracístico, enquanto que nos craniofaringiomas, a hiperintensidade relacionou-se somente com presença de cristais ou grumos de colesterol no líquido intracístico e não com as concentrações de proteínas ou lípides. Ao contrário do sugerido por alguns autores , nossos dados sugerem que a hiperintensidade de sinal nos craniofaringiomas relaciona-se à presença física de cristais de colesterol no líquido cístico e não à sua composição lipídica ou protêica. Os achados intracirúrgicos relacionam-se diretamente com aqueles sugeridos pela RNM.
MAGNETIC RESONANCE IMAGING, BIOCHEMICAL AND SURGICAL CORRELATION OF THE INTRA-CYSTIC CONTENTS IN SELLAR TUMORS
Najla Z. Halabi-Almeida; Fernando R. Pimentel-Filho; Márcia Nery; Luiz R. Salgado; Jayme Goldman; Bernardo Liberman; Arthur Cukiert.
Departments of Endocrinology and Neurosurgery, Hospital Brigadeiro-São Paulo
Sellar tumors frequently disclose solid and cystic components. The appearance of these cysts, as defined by MRI, can suggest the nature of the lesion. The hyperintensity found in many of these cysts by MRI had been attributed to their high content of protein, lipids or hemoglobin derivatives. Seven patients with cystic tumors of the sellar region (3 macroadenomas; 4 craniopharingiomas) who underwent high resolution MRI pre-operatively were studied. All patients were operated by the transesphenoidal or transcranial approach and in all the cystic fluid was aspirated before tumor removal and its proteic and lipidic content analised. The mean protein and lipid concentration in the macroadenomas were 7.1g /dl and 146.6 mg/dl, respectively. In the craniopharingiomas, these concentrations were 5.2 g/dl and 161 mg/dl, respectively. Within the macroadenomas, signal intensity correlated to the timing of previous hemorhage; in the craniopharingiomas, the hyperintensity correlated only to the presence of cholesterol cristals within the cystic fluid and not to the protein and lipid content. Contrary to what has been suggested by the few previous studies on the issue, our data suggest that the hyperintensity seen in craniopharingiomas is related to the presence of cholesterol crystals and not to the measured lipidic and proteic concentrations. The intraoperative findings are clearly well correlated to what was suggested preoperatively by MRI.
A. Cukiert, M. Andrioli, M. Nery, L. Salgado, J. Goldman, F. Pimentel, M. Knoepfelmacher, B. Liberman.
Departamentos de Neurocirurgia e Endocrinologia, Hospital Brigadeiro, Sao Paulo SP e Unidade Hipotálamo-Hipófise, Departamento de Endocrinologia, Hospital Clinicas USP, Sao Paulo SP, Brasil.
O estudo por imagem da região selar foi bastante facilitado após a introdução da tomografia computadorizada (TC) na prática clínica , mas foi somente o advento da ressonância magnética (RM) que realmente possibilitou o aparecimento de novos dados fisiológicos e patofisiológicos relacionados a esta região. A RM é capaz de delinear com clareza a região selar e suas estruturas circunjacentes , bem como o hipotálamo ventral, a eminência mediana e a haste hipofisária. Apesar de delimitar mal a interface seio cavernoso / pituitária, a RM é superior em todos os aspectos à TC no que diz respeito ao diagnóstico das patologias desta região, exceto na avaliação do envolvimento ósseo por tumores desta região (4,7,9).
As características clássicas do diagnóstico à RM e TC dos microadenomas pituitários incluem o desvio CONTRALATERAL da haste pituitária, hipodensidade (intensidade) e erosão do assoalho selar. O desvio contralateral da haste está usualmente relacionado ao efeito de massa do adenoma sobre a glândula normal, que encontra-se comprimida contralateralmente (1,2,6,8,11). Microadenomas medianos podem ter efeito de massa pequeno ou inexistente sobre a haste, que pode permanecer centrada nesta situação mas a ocorrência de desvio IPSOLATERAL da haste em direção ao tumor não foi ainda convenientemente estudado.
Este estudo relata pacientes portadores de microadenomas e que possuem desvio da haste hipofisária em direção ao tumor e discute a fisiopatologia destes achados aparentemente paradoxais.
Quatro pacientes adultos portadores de doença de Cushing e microadenomas pituitários e que possuíam RM com cortes coronais finos mostrando desvio IPSOLATERAL da haste em direção ao tumor foram estudados. Três pacientes já haviam sido submetidos à abordagem transesfenoidal de seus tumores secretores de ACTH (há 2, 6 e 8 anos atrás, retrospectivamente) e foram reoperados e um quarto paciente não havia sido operado anteriormente. Dois dos 3 pacientes (operados 6 e 8 anos atrás) que já haviam sido submetidos à cirurgia transesfenoidal obtiveram cura precoce porém tiveram recorrência de seus tumores originais e hipercortisolismo após a cirurgia inicial. O terceiro caso não obteve cura após o procedimento inicial e possuía ainda restos tumorais. Todas as reoperações foram realizadas por via transesfenoidal.
Havia recorrência do tumor no mesmo sítio primário em todos os pacientes já previamente operados. Nestes pacientes, A RM mostrava uma sela parcialmente vazia e tumor ocupando uma hemi-sela e a haste hipofisária desviada na direção do tumor (Figura 1). Nenhum deles possuía sinais de invasão do seio cavernoso. Dois destes pacientes entraram em remissão após a reoperação e o terceiro persistiu com hipercortisolismo e foi submetido à radioterapia e faz uso de ketoconazol (Tabela 1).
A RM do paciente não previamente tratado mostrava uma lesão cística com nódulo mural e desvio da haste hipofisária em direção ao cisto (Figura 2). À cirurgia, uma pequena quantidade de tumor foi vista ao lado do cisto que continha líquido amarelo-citrino e foi esvaziado. Não havia história prévia sugestiva de apoplexia desta paciente. Houve remissão do hipercortisolismo nesta paciente.
O estudo anátomo-patológico mostrou a presença de adenomas pituitários em todos os casos.
Todos os pacientes desta série possuíam desvio IPSOLATERAL da haste hipofisária em direção ao tumor. Eles podem ser segregados em 2 grupos distintos: aqueles já operados previamente e aqueles não tratados previamente.
Estes achados de RM parecem ser mais frequentes em pacientes já submetidos a procedimentos cirúrgicos prévios (12,14). Os achados clínicos e radiológicos sugerem que a haste hipofisária desviou-se “ex-vacuum” após o esvaziamento cirúrgico de uma hemisela à época da cirurgia primária, e permaneceu fixa nesta posição durante o período pós-operatório. Anos após, o tumor recorreu no mesmo sítio inicial e encontrou uma haste fixa, criando então uma situação paradoxal onde o tumor recorrente encontrava-se frente-a-frente à haste hipofisária. Neste contexto, o desvio IPSOLATERAL da haste seria uma característica pós-operatória da descompressão hemiselar.
Microadenomas císticos ou apopléticos não são comuns na doença de Cushing. Os cistos são mais comuns nos macroadenomas e em geral surgem após necrose sintomática ou assintomática seguida de reabsorção tumoral (3,5,10). Nosso paciente com tumor sólido/cístico não possuía história de apoplexia sintomática. Postulamos que este paciente tenha sofrido uma apoplexia assintomática, reabsorção parcial do tumor com significativa redução de seu tamanho e desvio “ex-vacuum” da haste pituitária. À época da formação do cisto, restou somente uma pequena porção do tumor, que agora encontrava-se frente-a-frente à haste.
O desvio CONTRALATERAL da haste persiste como padrão-ouro para o diagnóstico de microadenoma pituitário (13). Por outro lado, desvio IPSOLATERAL da haste pode ser visto à RM, especialmente em pacientes já previamente tratados por via transesfenoidal e não descarta a presença de tumor residual / recorrente no sítio primário.
DESVIO IPSILATERAL DA HASTE HIPOFISÁRIA EM PACIENTES COM MICROADENOMA
A. Cukiert, M. Andrioli, J. Goldman, M. Nery, L. Salgado, M. Knoepfelmacher, F. Pimentel, B. Liberman.
Serviços de Neurocirurgia e Endocrinologia do Hospital Brigadeiro, São Paulo SP e Unidade Hipotálamo-Hipófise da Disciplina de Endocrinologia, Hospital Clínicas USP, São Paulo SP, Brasil
O diagnóstico clássico de microadenoma inclui a presença de desvio da haste para o lado contrário ao tumor, erosão selar localizada e massa intra-selar de captação distinta da glândula normal. Descrevemos 4 pacientes portadores de microadenomas e que possuíam imagem de ressonância magnética que incluía o desvio da haste PARA O LADO do tumor. Todos os pacientes eram portadores de Doença de Cushing e 3 deles já haviam sido operados previamente em outro serviço. Nestes pacientes que já haviam sido operados, notava-se a presença da glândula na hemisela contrária ao tumor, e a presença do resto tumoral de espessura menor que da glândula na outra hemisela e a haste deslocada em direção ao tumor. Nesta situação, parece ter havido remoção de tumor na cirurgia inicial, quando então a haste desviou-se na direção da hemisela esvaziada, fixando-se nesta posição. Com a rescidiva tumoral, a haste aparece nesta mesma posição, apontando para o tumor, já que a mesma encontra-se fixa (fixação pós-operatória). No quarto paciente, o achado intraoperatório correspondeu a tumor com componente cístico (pós-necrótico) e sólido. Possivelmente tratava-se de adenoma apoplético com cavitação, sendo que a haste desviou-se como retração após diminuição do volume tumoral pós-apoplexia. Haste desviada para o outro lado do tumor persiste como bom parâmetro para localizar microadenomas. No entanto, em situações especiais (apoplexia tardia, pós-operatório) o oposto pode ocorrer e não afasta a presença de tumor.
IPSILATERAL DEVIATION OF THE PITUITARY STALK IN PATIENTS WITH PITUITARY MICROADENOMAS.
A. Cukiert, M. Andrioli, M. Nery, L. Salgado, J. Goldman, F. Pimentel, M. Knoepfelmacher, B. Liberman.
Departments of Neurosurgery and Endocrinology, Hospital Brigadeiro, Sao Paulo SP and Hypothalamus-Pituitary Unit, Department of Endocrinology, Hospital Clinicas USP, Sao Paulo SP, Brazil.
The radiological gold-standard for the diagnosis of pituitary microadenoma included a contralateral deviation of the pituitary’s stalk, hipointensity and sellar erosion. We describe 4 patients with microadenoma in whom MRI findings disclosed IPSILATERAL deviation of the pituitary’s stalk. All patients had Cushing’s disease and 3 had already been operated elsewhere. In these patients already submitted to surgery, the gland could be seen in one hemi-sella while tumor was detected at the other side and the pituitary stalk was deviated towards the tumour. These features suggested that stalk deviation in these patients would be a post-operative feature representative of previous surgical hemisellar decompression and tumour recurrence. The fourth patient has never been operated before. MRI showed a solid/cystic tumor with the pituitary’s stalk deviated towards the cyst. There was no clinical hystory of pituitary apoplexy. We postulated the occurrance of a sub-clinical apopleptic episode with tumour reabsorption, size reduction, cyst formation and “ex-vacuum ” stalk deviation towards the cyst. Contralateral deviation of the pituitary’s stalk remains the classical feature for the diagnosis of microadenomas. On the other hand, the opposite could occur, especially in patients already operated upon and could not rule out the presence of recurrent tumour.
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Figura 1 – RM com corte coronal em T1 mostrando a pituitária comprimida em uma hemisela e tumor ocupando a outra com a haste desviada em direção ao tumor. Estes achados ocorreram nos pacientes já tratados por via transesfenoidal.
Figura 2 – RM com corte coronal em T1 mostrando um tumor sólido / cístico ocupando uma hemisela e a pituitária ocupando a outra. A haste encontrava-se desviada na direção do componente cístico do tumor.
Tabela 1 – Resumo clínico dos pacientes desta série.
A. Cukiert, M. Andrioli, J. Goldman, M. Nery, L. Salgado, M. Knoepfelmacher and B. Liberman
Departments of Endocrinology and Neurosurgery, Hospital Brigadeiro, Sao Paulo SP, Brazil.
Cavernous sinus invasion by pituitary adenomas has been noted since the early days of pituitary surgery (1). On the other hand, the pre-operative diagnosis of cavernous sinus invasion was rarely done before the introduction of CT scanning in the clinical practice and correctly performed only in the more obvious cases by means of CT (2). The availability of high resolution MR imaging (3) has made it possible to study the sellar region in a detail not possible using CT scans (4).
Different criteria have been suggested to standardize the neuroradiological diagnosis of cavernous sinus invasion by pituitary adenomas (5,6). Unfortunately, the pituitary / medial wall of the cavernous sinus interface is poorly visualized even with MRI and that explains why no definite criteria have been accepted so far.
The prevalence of radiological and surgical findings compatible with cavernous sinus invasion has been increasing over the last decades. This plays an important role while treating these patients since cavernous sinus invasion is usually related to uncomplete surgical removal of the tumour, poor endocrinological results and the need for adjuvant therapy, especially the different types of radiation therapy.
This study reports the MRI findings in patients with pituitary macroadenomas and try to establish guidelines for the neuroradiological pre-operative diagnosis of cavernous sinus invasion in such patients.
Seventeen patients with pituitary macroadenomas (2 prolactinomas, 4 with Cushing’s disease, 7 with acromegaly and 4 with non-secreting tumors) that were submitted to transesphenoidal tumour resection and had intraoperative confirmation of cavernous sinus invasion were included in this study. Intraoperative diagnosis of cavernous sinus invasion was based on the visual inspection of this structure and clear signs of invasion. Discoloured or rough medial walls were not rated as “invasion”.
Pre-operative MRI scanning consisted of multiple T1 coronal slices through the sellar region with and without the administration of paramagnetic contrast. Post-contrast thin T1 axial slices of the sellar region were also obtained. A sagittal sequence was acquired for diagnostic purposes but was not used to define cavernous sinus invasion.
Different MR features were especifically studied in coronal (presence of tumor lateral to the carotid artery, within the carotid syphon and loss of the ring enhancement of the medial wall of the cavernous sinus) and axial (oppening of the double posterior leaflets of the cavernous sinus) slices.
In 8 patients, MRI disclosed tumor lateral to the carotid artery; 13 patients had tumor located within the carotid syphon and all had loss of the ring enhancement of the medial wall of the cavernous sinus as defined by MRI . In 10 patients, opening of the double posterior leaflets of the cavernous sinus could be seen in axial slices.
Only 1 (GH-secreting) of the 13 patients with secreting tumors with cavernous sinus invasion was cured by surgery alone. This patient had a progressive decline in GH levels over the first week and probably had a subacute necrosis of intracavernous tumour. All patients with secreting tumours not cured by surgery alone (n=12) were submitted to post-operative radiation therapy.
The presence of tumor lateral to the carotid artery in patients with pituitary adenomas has been considered the classic gold-standard for the pre-operative radiological diagnosis of cavernous sinus invasion (7). It is present in the bigger tumours (8,9). On the other hand, it is conceivable that if tumour can be often seen lateral to the carotid artery, that it could have been seen medial to it or within the carotid syphon in an earlier phase. Actually, the challange today is to define guidelines to identify early invasion of the cavernous sinus by pituitary tumors.
We have studied patients with pituitary macroadenomas. In these patients, lack of the ring enhancement of the medial wall of the cavernous sinus seems to be the first sign of cavernous sinus invasion and was seen in all patients. Tumor within the carotid syphon was also seen in the majority of the cases and seems to be related to a more advanced stage of invasiveness. The posterior leaflets of the cavernous sinus were also frequently widened, as could be seen in axial slices. Axial slices are not routinely acquired in MR imaging of the sellar region but it should be included in the protocol if cavernous sinus involvement is suspected. The prevalence of the reported cavernous sinus invasion by pituitary tumours have risen in recent years. It is probably even higher then the presently reported (10). It should be noted that microscopic dural invasion can be seen in patients in whom the surgeon reported no intraoperative invasiveness (11).
This study did not include microadenomas but patients with microadenomas can also have cavernous sinus invasion (12). This situation might correlate to the 10% failure rate for endocrinological cure in patients with microadenomas. We are presently carrying out the evaluation of the meaning of early signs of cavernous sinus invasion as defined by MRI in the prognosis of patients with microadenomas.
Interestingly, the only (acromegalic) patient with cavernous sinus invasion cured by surgery had a sub-acute cure which is quite different from what is seen conventionally in patients cured by surgery, especially in tumours which secrete hormones with a very small half-life ( e.g., GH). We postulated that this patient has had a progressive post-manipulation necrosis of the intracavernous portion of the tumour and achieved cure.
The multiple radiological patterns of cavernous sinus involvement requires an individualized analysis of each patient. Imaginary lines and compartments are not useful to standardize this diagnosis (13).
Only 3 patients disclosing the presently analyzed MRI criteria for cavernous sinus (CS) invasion and with intraoperative findings not confirming CS invasion were found in a series of 250 patients. Taken together with the data from this study, it seems that the analised MR criteria in macroadenomas could provide useful guidelines for the pre-operative diagnosis of cavernous sinus invasion and patients’ counselling. How these features apply to microadenomas has yet to be seen.
The endocrinological results obtained in patients with cavernous sinus invasion (only 7% of remission) by macroadenomas are in marked contrast to those obtained in non-invasive adenomas. Our data showed that endocrine remission can be expected in 90% of non-invasive microadenoma and in 70% of non-invasive macroadenomas.
- Martins AN, Hayes GJ and Kempe LG. Invasive pituitary adenomas. J Neurosurg 1965;22:268-276.
- Nichols DA, Laws ER, Houser OW and Abboud CF. Comparison of MRI and CT in the preoperative evaluation of pituitary adenomas. Neurosurgery 1988;22:380-385.
- Daniels DL, Czervionke LF, Bonneville JF, Cattin F, Mark LP, Pech P, Hendrix LE, Smith DF, Haughton VM and Williams AL. MR imaging of the cavernous sinus: value of spin-echo and gradient recalled echo images. A J Roentgenol 1988;151:1009-1014.
- Davis PC, Hoffman JC, Spencer T, Tindall GT and Braun IF. MR imaging of pituitary adenoma: CT, clinical and surgical correlation. A J Roentgenol 1987;148:797-802.
- Komiyama M. MRI of the cavernous sinus. Radiat Med 1990;8:136-144.
- Komiyama M, Hakuba A, Yasui T, Yagura H, Fu Y, Baba M and Nishimura S. MRI of intracavernous pathology. Neurol Med Chir Tokyo 1989;29:573-578
- Ahmadi J, North CM, Segall HD, Zee CS and Weiss MH. Cavernous sinus invasion by pituitary adenomas. A J Roentgenol 1986;146:257-262.
- Kaufman B, Kaufman BA, Arafah BM, Roessmann U and Selman WR. Large pituitary gland adenomas evaluated with MRI. Neurosurgery 1987;21:540-546.
- Scotti G, Yu CY, Dillon WP, Norman D, Colombo N, Newton TH, Groot J and Wilson CB. MR imaging of cavernous sinus involvement by pituitary adenomas. A J Roentgenol 1988;151:799-806.
- Selman WR, Laws E, Scheithauer E and Carpenter S. The occurrence of dural invasion in pituitary adenomas. J Neurosurgery 1986;64:402-407.
- Daita G, Yonemasu Y, Nakai H, Takei H and Ogawa K. Cavernous sinus invasion by pituitary adenomas-relationship between MRI findings and histologically verified dural invasion. Neurol Med Chir Tokyo 1995;35:17-21.
- Hirohata T, Uozumi T, Mukada K, Arita K, Kurisu K, Sumida M, Yano T, Takechi A and Onda J. Microprolactinoma invading the cavernous sinus. Report of 3 cases. Neurol Med Chir Tokyo 1992;32:10-12.
- Knosp E, Steiner E, Kitz K and Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classsification compared to surgical findings. Neurosurgery 1993;33:610-618.
Intra-operative abnormal acth and cortisol dynamics in patients submitted to transesphenoidal surgery for acth-secreting pituitary adenomas
Fernando Pimentel, Bernardo Liberman, Arthur Cukiert, Jayme Goldman, Luis Roberto Salgado
The most important endocrinological response to surgical stress includes activation of the hypothalamic-pituitary-adrenal (HPA) and sympathetic systems. No major hormonal change occurs during anesthesia and surgical exploration. However, during anesthesia reversal, endotracheal extubation and in the immediate post-operative recovery period a strong activation of the HPA axis and adrenomedullary sympathetic system can be observed with substantial increases in plasma ACTH, cortisol and epinephrine (Udelsman 87). A limited number of papers that studied the responses of these systems to surgical stress had included patients with pituitary tumors (Arafah e trab com D.Cush), but no previous study had evaluated, in these patients, the influences on ACTH and cortisol secretion rates of the mechanical pituitary manipulation.
In this paper we report on the intraoperative ACTH and cortisol dynamics in patients submitted to transesphenoidal surgery (TS) for ACTH-secreting pituitary tumors as compared to those with other sellar tumors.
SUBJECTS AND METHODS
Twenty-one patients with pituitary tumors were evaluated before and after TS. All patients received identical sedative and anesthetic agents. Imaging of the pituitary tumors was obtained by magnetic resonance (MR) in all patients. Suggestive tumor tissue was visualized and resected by the neurosurgeon during surgery and histological examination and immunohystochemistry confirmed the diagnosis in all patients. Informed consent was obtained from all patients and the research protocol was approved by the Institutional Review Board.
They were divided in 2 groups according to their pre-operative HPA axis function and tumor type. Group I patients (n= 9; age = ; 3 males and 6 females) had GH-secreting and non-secreting adenomas. All patients had a normal cortisol response during an insulin tolerance test (ITT) obtained in the pre-operative period and these patients did not receive hydrocortisone (HC) during surgery or in the post-operatives days. Group II patients had ACTH-secreting pituitary tumors (n = 12; age = ; 2 males and 10 females). Ten patients had Cushing’s disease and 2 had Nelson’s syndrome. Group II patients received intravenous HC during surgery and in the first post-operative day, as follows: 200 mg during the day of surgery (PO-i)(50 mg immediatly before pituitary manipulation, 50 mg 10 minutes after pituitary tumor ressection and 50 mg b.i.d.) and 100 mg during the first post-operative day (PO-1) (50 mg b.i.d.).
Blood samples for cortisol and ACTH determination were obtained from all patients before anesthesia, immediatly before pituitary gland manipulation, 10 minutes after pituitary tumor resection and 30, 60, 90, 120 and 150 minutes after tumor removal. In Group I patients an additional blood sample was obtained 300 minutes after tumor removal.
Two Group II patients (one with Cushing’s disease and one with Nelson’s syndrome) were also studied using a similar protocol pre-operatively in a resting state. They received 200 mg of intravenous HC in a schedule similar to that during surgery and blood samples were obtained before and after HC injections at the same timing.
Serum cortisol and plasma ACTH were measured by an automated chemiluminescent enzyme immunoassay kit (IMMULITE, Diagnostic Products Corp., Los Angeles, CA) and the reference range was 5-25 m g/dL and 10-46 pg/mL for cortisol and ACTH, respectively. The inter- and intra-assay escrever por extenso (CV) for cortisol was 6.0% and 4.1%, respectively. For ACTH the CV inter-assay was 7.2% and the intra-assay CV was 2,9%.
Data were analyzed by the Mann-Whitney test, Wilcoxon test and 2-way ANOVA for repeated measures (on one dimension), and Kelss-Newman’s multiple range test. Results were reported as mean +/- SE. P-Values below 0.05 were considered statistically significant.
Mean ACTH and cortisol values observed in the preoperative evaluation were significantly smaller in group I (ACTH= 47.8 +/- 7.4 pg/mL and cortisol= 16.3 +/- 1.9 m g/dL) than in group II (ACTH = 82.5 +/- 15.6 pg/mL and cortisol = 32.3 +/- 4.5 m g/dL).
In group I, the mean ACTH value 10 minutes after pituitary tumor resection (ACTH = 69.8 +/- 11.7 pg/mL) was significantly greater than that in the pre-pituitary manipulation period (ACTH =29.2 +/- 8.2 pg/mL). This increase in ACTH level was observed after tumor resection and persisted for more than 150 minutes. The ACTH level fell into the normal range in all patients during PO-1 (figure 1). A significant increase in the cortisol level was observed 60 minutes after tumor resection, which persisted for at least 150 minutes.
In group II, mean ACTH values were also significantly greater 10 minutes after pituitary tumor resection (297.8 +/- 75.1 pg/mL) than in the pre-manipulation period (ACTH= 115.4 +/- 26.2 pg/mL). This occurred despite the administration of 50 mg of HC before pituitary manipulation. No differences in mean ACTH concentration were found within the first 5 hours after tumor resection either in the 6 patients with complete tumor resection (proved later by the remission of hypercortisolism in 5 patients with Cushing disease or ACTH normalization in a patient with Nelson’s syndrome) (mean ACTH = 153.9 +/- 46.4 pg/mL) or in other 6 patients not cured by surgery (mean ACTH = 161.2 +/- 71.2 pg/mL) (p= 1.0). Only in PO-1 a significant decrease in ACTH level was observed in these patients (9/12 had a normal ACTH level). Both patients with ACTH-secreting tumors (one with Cushing’s disease and other with Nelson’s syndrome) studied in a resting state pre-operatively were cured by surgery. They showed a clear decrease in ACTH concentration after HC administration pre-operatively. This was not observed intra-operatively. ACTH levels after tumor resection in patients with Nelson’s syndrome followed the same pattern as observed in patients with Cushing’s disease and statistical results were the same when they were excluded from the sample.
Increased ACTH and cortisol secretion during anesthesia reversal, endotracheal extubation and early recovery has been well docummented in some reports dealing with major surgical procedures (Arafah, Udelsman, Estep 62). They are considered the main periods of stress to the patient. We noted a robust ACTH release in our patients with non-secreting tumors during TS during these periods.
It is well known that in normal subjects in a resting state steroid administration supresses ACTH. We found that HC may partially suppress ACTH secretion in patients with ACTH-secreting pituitary tumors. On the other hand, in conditions of stress (surgery) corticotrophs may secrete high amounts of ACTH in spite of the excess of circulating steroids as in group II patients, suggesting that during stress the behavior of the human HPA system may not conform to the specifications of a rigid negative feedback mechanism (Step).
An abrupt decline in ACTH level should be expected within 15-30 min (approximately one half-life)(referencia 6 doFaff 95) if tumor resection was complete and corticotrophs were totally suppressed. However, even in those 6 patients cured by surgery (including 1 patient with Nelson’s syndrome) persistently high ACTH levels could be seen at least 5 hours after tumor resection. This suggests that peri-tumoral normal corticotrophs may not be totally suppressed in patients with Nelson’s syndrome or Cushing’s disease. We observed a rise in ACTH levels during the first post-resection hours in patients with Cushing’s disease who were cured by TS. Graham et al did not observe a significant reduction in ACTH levels for hours after complete tumor resection. Mechanical pituitary manipulation may justify the early rise in ACTH levels, as showed in the present study, but it could not explain the maintenance of high ACTH levels for hours (ACTH half-life = 8-15 minutes). Its not clear which ACTH-releasing factor could be leading to this abnormally set feedback mechanism during surgical stress. Several substances secreted during surgical stress may induce ACTH release such as CRH, vasopressin, angiotensin-II, catecholamines and interleukin-1 and 6 ( Udelsman 87, Salem 94 e trab da Martha). Some of these substances could be acting as a potent ACTH-releasing factors. Durijk et al ( 97 ) showed that administration of a supra-physiological dose of HC (80 mg) suppressed the lipopolysaccharide-induced interleukin-1B, interleukin-6 and tumor necrosis factor (TNF) alfa production, whereas administration of a physiological dose (20 mg) of HC suppressed only TNF-alfa production. In the present study, a similar supra-physiological dose of HC was administered in patients with ACTH-secreting tumors and it is possible that all 3 citokines were suppressed during surgical stress. At least in these cases, the persistent ACTH release could not be exclusively due to these citokines. ACTH and cortisol hypersecretion occurred in the post-operative period of neck exploration procedures despite the absence of increased circulating CRH (Udelsman 87). Udelsman and col (1987) showed significant increase in epinephrine and in plasma renin activity during this period and they should be considered pottentially important ACTH-releasing factors. However, plasma elevations of catecholamines during acute glucocorticoid deficiency after surgical treatment for Cushing’s disease (abstract ICE 96) are not enough to induce an adequate increase in ACTH levels. We noted (umpublished data) that in a patient with cortisol-secreting adrenal adenoma there was no ACTH increase after surgery, suggesting that in this situation corticotrophs were completely suppressed or that some ACTH-releasing factors secreted during TS were not released during adrenalectomy. Persistent ACTH secretion during the immediate post-operative period in patients with ACTH-secreting pituitary tumors may be induced by so far unknown ACTH-releasing factors.
Peri-tumoral normal corticotrophs are not completely suppressed in patients with Cushing’s disease. This is also true during the immediate post-operative stress period and with the administration of high doses of glucocorticoids. ACTH-releasing factors other than the traditional ones may be responsable in these patients for the persistent ACTH release during TS. In patients with ACTH-secreting pituitary tumors the behavior of the human HPA system during TS does not conform to the specifications of a negative feedback mechanism, as can be seen in patients without ACTH-secreting tumors. Mechanical pituitary manipulation may induce ACTH release in patients with ACTH-secreting pituitary tumors but probably does not interfer in the maintenance of high ACTH-levels during the early post-operative period.
SOMATOTROPHIC AND CORTICOTROPHIC FUNCTION OUTCOME AFTER TRANSESPHENOIDAL SURGERY IN PATIENTS WITH SELLAR TUMORS AND PRE-OPERATIVE ENDOCRINE DEFICITS
Pinheiro MM1, Cukiert A, Salgado LR, Nery M, Goldman J, Pimentel F, Liberman B.
Acute pituitary apoplexy is a rare event, even in patients with pituitary macroadenomas. On the other hand, the presence of necrotic/hemorrhagic areas, especially in macroadenomas, seems to be more common than earlier reported in the CT period. After the introduction of MR in the presurgical workup of these patients, these apopleptic areas have been more easily diagnosed preoperatively. Forty consecutive patients with pituitary macroadenomas were studied with high-resolution 1.5 T T1 coronal, sagittal and axial slices over the sellar region. Special attention was paid in the detection of necrotic, cystic and hemorrhagic areas within these tumors. Ten patients had hemorrhagic/necrotic areas within their tumors, without any sign or symptom of acute apoplexy. These areas varied from small (2 mm) to very large (30 mm) ones. Seven patients had non-secreting tumors, 2 GH and 1 prolactin secreting tumors, which is the same profile of secretory pattern for the whole series (40 patients). The clinical picture included (other than that caused by endocrine secretion) slowly progressive (but not acute) visual loss (n = 8) and headache (n = 3). After surgical decompression of the surrounding structures and visual apparatus, which was facilitated by the presence of the necrotic areas, there was visual improvement in 6 patients and headache resolution in 2. The presence of asymptomatic apopletic areas in these macroadenomas and their absence in microadenomas as can be seen in the literature suggest that they are related more to the size of the tumor than to its endocrine secretion pattern. This is in agreement with a vascular insufficiency hypothesis in the pathogenesis of these lesions.
SOMATOTROPHIC AND CORTICOTROPHIC FUNCTION OUTCOME AFTER TRANSESPHENOIDAL SURGERY IN PATIENTS WITH SELLAR TUMORS AND PRE-OPERATIVE ENDOCRINE DEFICITS
Fernando R. Pimentel-Filho, Luis Roberto Salgado, Arthur Cukiert, Bernardo Líberman.
Serviço de Endocrinologia e Neurocirurgia do Hospital Brigadeiro- São Paulo – SP.
Sixteen patients with sellar tumors that were treated surgically and who had pre-operative somatotrophic and corticotrophic function deficits were submitted to pre- and early post-operative ITTs. Seven patients had non-functioning adenomas, 5 had prolactinomas, 3 had craniopharyngioma and 1 had cordoma of the clivus. All patients had macro-tumors and none received radiotherapy within the studied period. Seven patients had GH, 4 had cortisol and 5 had both GH/cortisol function pre-operative deficit. Five patients with isolated GH, 4 with isolated cortisol and 3 with both GH/cortisol deficiencies showed a postoperative functional recovery. New cortisol secretion deficits were observed in 2 patients postoperatively and both required long-term steroid replacement. These data suggest that preoperative endocrine deficits may be reversible after surgical decompression of the sellar region and that new endocrine deficits are rarely seen after surgery. All such patients should be tested postoperatively from an endocrinological point of view to reevaluate the need for replacement therapies.
Dezesseis pacientes portadores de tumores da região selar que foram tratados cirurgicamente e que possuíam deficits funcionais dos eixos somatotrófico ou corticotrófico foram submetidos a teste de tolerância à insulina pré- e pós-operatoriamente. Sete pacientes possuíam adenomas não-funcionantes, 5 possuíam prolactinomas, 3 craniofaringiomas e 1 possuía cordoma de clivus. Todos os pacientes possuíam macro-tumores e nenhum deles foi submetido à radioterapia durante o período do estudo. Sete pacientes possuíam deficiência isolada do setor somatotrófico, 4 isolada do setor corticotrófico e 5 possuíam deficiência de ambos os setores. Cinco pacientes com deficiência isolada do setor somatotrófico, 4 com deficit isolado do setor corticotrófico e 3 com ambos setores deficientes obtiveram melhora funcional pós-operatoriamente. Novos deficits do setor corticotrófico ocorreram em 2 pacientes, que necessitaram reposição de esteróides por longo prazo. Estes dados sugerem que deficits endócrinos pré-operatórios podem ser revertidos pela descompressão cirúrgica da região selar e que novos deficits causados pela cirurgia são raros. Estes pacientes devem ser retestados pós-operatoriamente do ponto de vista endócrino para se determinar a necessidade de terapia de reposição hormonal.
Hypogonadotrophic hypogonadism and growth hormone deficiency (GHd) are the most common hormonal abnormalities in patients with tumors in the sellar region (1, 18). The pituitary-adrenal axis is less affected than the others by such tumors (1,18,19). Both improvement or worsening in one or more endocrine axis have already been documented after surgery for pituitary tumors with or without apoplexy (1,2,11,13,18,19). If hypothalamic or pituitary tissue has been destroyed recovery of normal function is unlikely, and lifelong hormone-replacement therapy is required. However, partial or complete recovery of pituitary function occurred in the majority of the patients (65%) with non-functioning pituitary adenomas submitted to transesphenoidal surgery studied by Arafah et al. (1); thyroidal function improved in 57%, gonadal function in 32% and pituitary-adrenal function in 38% of the patients (1). Somatotrophic function had fully recovered in only a small number of patients postoperatively (0-27%) (1,18,19). However, in most of these studies the adult GH deficiency has been defined based on studies in children and the wide variation in the “cut-off” of peak GH response to a standard provocative test could have contributed to this small rate of somatotrophic recovery.
The mechanisms by which pituitary tumors cause hypopituitarism include mechanical compression of normal pituitary tissue by the tumor, impaired blood flow to the normal tissue, and interference with the delivery of hypothalamic regulating hormones through the hypothalamic-hipophysial portal system.
In this paper we analised the effects of transesphenoidal surgery on somatotrophic and corticotrophic deficiencies seen in patients with sellar tumors and elaborated on the usefulness of re-evaluating these patients from an endocrinological point of view after surgery.
Sixteen patients (11 women and 5 men) who have undergone transesphenoidal surgery for the treatment of sellar tumors were retrospectively evaluated. Age ranged from 19 to 45 years (mean= 31 ( 2 years) and BMI was 24.4 ( 0.5 Kg/m2. All patients had GH or cortisol deficiencies as shown by an insulin tolerance test (ITT) preoperatively. No patient underwent radiotherapy. Seven patients had clinically nonfunctioning adenomas, 5 had prolactinomas, 3 had craniopharyngioma and 1 had a cordoma of the clivus. All patients had large tumors (with sellar and supra-sellar extention) demonstrated by computerized tomographic scanning. In one of the patients with craniopharyngioma the tumor presented solid and cistic components. Clinical symptoms suggestive of hypogonadism associated with reduced basal levels of gonadotrophins and estradiol (in women) or testosterona (in men) were observed in 12 of 16 patients preoperatively. No patient had clinical or biochemical signs suggesting hypothyroidism or other sistemic disorder.
All patients have undergone an ITT (0.1 U/Kg of regular insulin) to evaluate GH and cortisol secretion before and after surgery. After an overnight fast, an antecubital vein was punctioned early in the morning and kept patent by slow saline infusion. Basal blood sampling was performed 30 minutes afterwards and insulin was then administered in bolus. Subsequent samples were colected at 15, 30, 45, 60 and 90 minutes after insulin injection for glucose and hormonal levels determination. The postoperative evaluation was performed 3 months after surgery. Patients were kept out of any medication for at least 2 weeks before the test. Those who showed basal levels of cortisol below 5 ug/dl or a low response of cortisol to ITT preoperatively received cortisone acetate during surgery and in the immediate postoperative period, which was progressively tappered down within the first postoperative week whenever possible.
Serum GH concentrations were measured by immunoradiometric methods, using a commercially available kit from Pharmaica (Uppsala, Sweden). The limit of detection of GH was 0.5 ng/ml, and the intra- and interassay coefficients of variation were 7.3% and less than 10%, respectively. The samples from the two tests (pre-and postoperative) from each patient were measured in the same assay. GHd was diagnosed if peak GH level did not reach a value of 5,0 ng/ml after insulin-induced hypoglycaemia (< 45 mg/dL) (12). Plasma concentrations of cortisol were measured by radioimmunoassay, using kits from Baxter-Clinical (Stillwater, MA), and the intra- and interassay coefficients of variation were 7.0% and 9.0%, respectively. The diagnosis of cortisol deficiency was established if the peak cortisol level was lower than 18 (g/dL following hypoglycaemia (3). The others hormonal measurements (T3, T4, TSH, LH, FSH and PRL) were performed by radioimmunoassay, using commercially available kits, which have interassay coefficients of variation below 12% (data not presented).
The Wilcoxon test was used to compare the peak GH and cortisol levels in the pre- and postoperative evaluations. The results were expressed in mean ( SEM values. A “p” value lower than 0.05 was considered statistically significant.
All patients got effective ITTs (glicaemia below 45 mg/dl). Twelve patients had GHd (7 with isolated GHd and 5 with GHd plus cortisol deficiency) and 4 had isolated cortisol deficiency. The preoperative mean GH peak for the 12 patients with GHd was 1.5 ( 0.2 ng/ml (range: 0.5 – 3.1). Postoperatively, 7 (58.3%) of these patients showed GH peaks higher than those observed preoperatively (11.6 ( 2.8 ng/ml)(p = 0.02), being between 5 to 7 ng/ml in 3 patients and above 7 ng/ml in the others (figure 1). Five out of the 7 patients with isolated GHd in the preoperative evaluation recovered GH secretion after surgery. The patients with cortisol deficiency had a mean cortisol peak of 9.5 ( 1.5 ug/dl preoperatively. Six of these patients (67%) disclosed a normal cortisol response during the ITT after surgery (peak cortisol = 23.4 ( 2.1 (g/dl)(p = 0.03) (figure 2). Three of the 5 patients with GH plus cortisol deficiencies preoperatively recovered some endocrine function after surgical treatment: 1 patient with prolactinoma recovered GH and cortisol secretion and the others 2 recovered only one endocrine function (GH or cortisol secretion).
Patients with isolated GH or cortisol deficiencies preoperatively had an 82% recovery rate after surgical treatment (9/11). In those with both GH and cortisol deficiencies before surgery, the rate of recovery of at least one of the pituitary axis was 60% (3/5).
Postoperative impaired cortisol secretion was observed in 2 patients with isolated GHd preoperatively and both required chronic steroid replacement therapy. Surgery did not induce GHd in those patients with isolated cortisol deficiency preoperatively. Table I shows the distribution of the preoperative hormonal deficiencies and the endocrine outcome after surgery. Five of the 7 patients with nonfunctioning macroadenomas recovered GH or cortisol secretion postoperatively. Only 1 of the 5 patients with prolactinoma remained with partial cortisol deficiency postoperatively and did not require chronic replacement therapy. Prolactin levels were reduced in all patients with prolactinoma after surgery and were normal in 3. The other 2 had prolactin levels of 1030 and 550 postoperatively. There was no statistical difference on the endocrine recovery rate between patients with prolactinoma with normal or abnormal postoperative prolactin levels. All patients with craniopharyngioma disclosed GHd before surgery and none had cortisol deficiency. One of them obtained a GH secretion recovery (with peak GH of 19.0 and 14.0 ng/ml in two postoperative ITT) but in 2 there was a worsening of the cortisol response to the ITT. The patient with cordoma recovery its GHd after surgical treatment.
GH release after an insulin-induced hypoglycaemia may be impaired in adult patients with sellar tumors. This can also occur after irradiation or surgery of this region (6,10,12,17,21,22,23). Although there is no consensus of which would be the best method to detect GHd in adults (6,7,12,21), Hoffman et al. (12) have demonstrated that the ITT is extremelly accurate in differentiating subjects with organic GHd from normal matched subjects. In Hoffman’s series, GHd adults had a GH peak lower than 3.1 ng/ml during the ITT, which is significantly lower than the control subjects that had GH peaks higher than 5.0 ng/ml. Furthermore, GH release after the ITT is not reduced in idiopatic hyperprolactinemia (9). Although some authors would consider the diagnosis of adult onset GHd in all patients with a GH peak lower than 7-10 ng/ml, the mean GH peak seen in most of their patients were lower than 3.5 ng/ml, suggesting that in this disorder the GH peak after ITT is very low (17,22,25). We have accepted Hoffman’s criteria for the diagnosis of adult-onset GHd in this paper. Surprisingly, our data showed that 58.3% of the patients with GHd preoperatively had an improvement in GH secretion (GH peak higher than 5.0 ng/ml) postoperatively. This rate of recovery after surgery is higher than previously reported (1,18,19). Arafah et al. (1) reported a high incidence of GHd (near 100%) preoperatively in patients with nonfunctioning pituitary adenoma and that GH secretion’s recovery was not frequent postoperatively (15%). The cutoff value for the diagnosis of GHd in our study (5.0 ng/ml) was lower than that used in their study (8.0 ng/ml) and this could have influenced our postoperative results. The same authors (1) had observed that the mean tumor size in patients recovering pituitary function was significantly smaller than that in patients with persistent hypopituitarism. Unfortunately, it is often difficult to compare different series in terms of tumor volume and size.
Many authors (5,8,16,18,24) have demonstrated that preoperative adenohypophyseal dysfunction was not reversed by surgery in most of patients with craniopharyngioma and that most of them experienced new endocrinological deficits after surgery. However, Barreca et al. (4) reported GH secretion recovery postoperatively in patient with craniopharyngioma. One of our patients with craniopharyngioma also recovered the somatotrophic function postoperatively .
Pituitary-adrenal function improved in 67% of our patients with preoperative ACTH deficiency. Immediate recovery of pituitary-adrenal function has been described previously in approximatly 65% of the patients with macroadenomas (3). Pituitary ACTH secretion deficits or impaired ACTH reserve is not as frequent as GH deficiency preoperatively in patients with sellar tumors. ACTH secretion deficiency has been described in 5-62% of the patients with macroadenomas or craniopharyngioma (1,18,19). Moreover, postoperative pituitary-adrenal deficiency is not so frequent (3,13). Two of our patients with craniopharyngioma developed permanent ACTH deficiency postoperatively and one patient with prolactinoma remained with partial deficiency that did not require steroid replacement for a long time.
The pathophysiological mechanisms causing partial or total hypopituitarism in patients with sellar tumors are not yet completely understood. The recovery of pituitary function in most patients after transesphenoidal surgery suggest that there is viable pituitary tissue preoperatively, which is transiently unable to secrete, possibly as a result of altered hypothalamic regulation (1,3). It is possible to demonstrate some preserved pituitary function with the use of sinthetic hypothalamic peptides like GHRH, TRH and GnRH in patients with hypothalamic-pituitary disconnection due to pituitary stalk transection or tumors of this area (14,20). It has been showed that the preoperative serum prolactin level is higher in patients who recovered pituitary function after adenomectomy than in those who did not (1,3). High intrasellar pituitary tissue pressure and pituitary stalk compression were previously demonstrated (15) and could be the most important factor to induce pituitary deficiencies by comprimising blood flow through the portal vessels. Surgery with removal of the tumor could induce decompression of the pituitary stalk and reduce intrasellar pituitary pressure, allowing for the recovery of some or all hypothalamic-pituitary axis.
In summary, this study demonstrated that in patients with sellar tumors preoperative cortisol and GH deficiencies may be reversible after surgical decompression and that hormonal deficiency is not frequently induced by surgery. All such patients should be tested postoperatively from an endocrinological point of view to reevaluate the need for replacement therapies.
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- Hout WB, Arafah BM, Salazar R, Selman W. Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: Is perioperative steroid therapy necessary( J Clin Endocrinol Metab 1988: 66: 1208-1212.
- Kikuchi K, Fujisawa I, Momoi T at all. Hypothalamic-pituitary function in growth hormone-deficient patients with pituitary stalk transection. J Clin Endocrinol Metab 1988: 67: 817-823.
- Lees PD, Pickard JD. Hyperprolactinemia, intrasellar pituitary tissue pressure, and the pituitary stalk compression syndrome. J Neurosurg 1987; 67: 192-196.
- Newman CB, Levine LS, New MI. Endocrine function in children with intrasellar and suprasellar neoplasms. Am J Dis Child 1981; 135: 259-262.
- Orme SM, Sebastian JP, Oldroyd B, Stewart SP, Grant PJ, Stickland MH, Smith MA, Belchetz PE. Comparison of measures of body composition in a trial of low dose growth hormone replacement therapy. Clin Endocrinol (Oxf) 1992; 37: 453-459.
- Paja M, Lucas T, Garcia-Uria J, Salamé F, Barceló B, Estrada J. Hypothalamic-pituitary dysfunction in patients with craniopharyngioma. Clin Endocrinol 1995; 42: 467-473.
- Pelkonen R, Grahne B, Hirvonen E, Karonen S-L, Salmi J, Tikkanen M, Valtonen S. Pituitary function in prolactinoma. Effect of surgery and postoperative bromocriptine therapy. Clin Endocrinol 1981; 42: 467-473.
- Poppovic V, Damhanovic S, Micic D, Djurovic M, Dieguez C, Casanueva FF. Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: Evidence that GHRP-6 main action is exerted at the hypothalamic level. J Clin Endocrinol Metab 1995; 80: 942-947.
- Reutens AT, Hoffman DM, Leung K-C, Ho KKY. Evaluation and application of a highly sensitive assay for serum growth hormone (GH) in the study of adult GH deficiency. J Clin Endocrinol Metab 1995; 80: 480-485.
- Rosen T, Bosaeus I, Tolli J, Lindstedt G, Bengtsson BA. Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency. Clin Endocrinol (Oxf) 1993; 38: 63-71.
- Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-1803.
- Thomsett MJ, Conte FA, Kaplan SL, Grumbach MM. Endocrine and neurologic outcome in childhood craniopharyngioma: review of effect of treatment in 42 patients. J Pediatr 1980; 97: 728-735.
- Whitehead HM, Boreham C, Mcllrath EM, Sheridan B, Kennedy L, Atkinson AB, Hadden DR. Growth hormone treatment of adults with growth hormone deficiency: results of a 13 month placebo controlled cross-over study. Clin Endocrinol (Oxf) 1992; 36: 45-52.
Sellar floor reconstruction after transsphenoidal surgery using fibrin glue without grafting or implants: technical note
Seda L1, Camara RB, Cukiert A, Burattini JA, Mariani PP.
Different techniques have already been described for reconstructing the sellar floor after transsphenoidal (TS) procedures. This paper reports on the use of fibrin glue alone without grafting or the use of implants in the reconstruction of the sellar floor after TS.
Five hundred sixty-seven patients who submitted to TS for pituitary and sellar region tumors were studied. No intraoperative cerebrospinal fluid (CSF) leak occurred in 503 patients (group 1); in the remaining 64 patients (group 2), intraoperative CSF leak was noted. In group 1 patients, closure of the sellar floor consisted of packing the surgical bed with hemostatic material only. When CSF leak was noted, the surgical bed was covered with a layer of hemostatic material and the intrasellar space was filled up with fibrin glue. An additional layer of hemostatic material was added at the topography of the preexisting sellar floor, and a second amount of fibrin glue was applied over it. At the end of surgery, a continuous lumbar CSF drainage system was installed in group 2 patients and kept for 5 days. Prophylactic antibiotics were administered during this period.
We did not observe delayed CSF leak, meningitis, or visual loss in group 1 patients. In group 2, 2 patients presented with complications: 1 patient got meningitis but no overt CSF leak, and the other disclosed a delayed postoperative leak treated by reoperation.
Our results showed that closure of the sellar floor with hemostatic material and fibrin glue without grafting or the use of implants is a safe and efficient method to prevent postoperative complications after TS. Generally speaking, there is no need for grafting or the use of implants at the end of TS.
Pituitary-adrenal dynamics after ACTH-secreting pituitary tumor resection in patients receiving no steroids post-operatively
Pimentel-Filho FR1, Silva ME, Nogueira KC, Berger K, Cukiert A, Liberman B.
It has recently been suggested that the classical routine of glucocorticoid administration before and after transsphenoidal surgery (TSS) in Cushing’s disease (CD) patients may not be necessary, since it is likely that peritumoral normal corticotrophs are not completely suppressed during this period. We compared the dynamics of ACTH and cortisol from a group of CD patients (cured and not cured), receiving no steroids post-operatively, with a control group of acromegalic patients who presented normal hypothalamic-pituitary-adrenal (HPA) axis. Blood samples for ACTH and cortisol determination were obtained immediately before, at the end of surgery and at 4, 8, 12, 16, 24, 48 and 72 h after surgery, in 8 cured CD patients (Group I), 9 not cured CD patients (Group II) and in 7 subjects with acromegaly (Group III) who presented normal HPA axis (control group). The mean ACTH level in Group I was significantly lower than in Group III from 4 to 12 h and lower than in Group II from 8 to 12 h post-operatively. The mean cortisol level in Group I was lower than in Groups II and III from 8 to 72 h after surgery. No difference in mean cortisol level was observed among Groups II and III during the evaluated period. The lowest cortisol value in Group II was 193 nmol/l (at 24 h after surgery) and in Group I patients, after 20 h post-operatively, the highest cortisol level was 165 nmol/l. Although all cured CD patients (Group I) presented serum cortisol level lower than 55 nmol/l until 72 h after surgery, none had significant complications related to adrenal insufficiency. Ours findings are in agreement with recent observations that there is probably no need for glucocorticoid administration until clinical and/or laboratorial data are suggestive of adrenal insufficiency. However, we have also shown that a subphysiological HPA axis response could be observed in cured CD patients after TSS, and a definitive conclusion about glucocorticoid management during and after this procedure could not be made on the ground of the few cases studied in the literature.
Miranda M1, Barros L, Knopfelmacher M, Augusto EC, Jacomossi A, Cukiert A, Salgado LR, Nery M, Goldman J, Liberman B.
Pituitary apoplexy is rare and endocrine remission in patients with apopletic secreting pituitary adenomas is even rarer. This study reports on two patients with pituitary macroadenomas (one with Cushing’s disease and the other with acromegaly) in whom endocrine remission occurred after apoplexy. The first patient had Cushing’s disease and had an ictus of headache and vomiting after which she started a progressive remission of hypercortisolism. A post-apoplexy MRI disclosed persistence of a sellar and supra-sellar mass. She was submitted to transesphenoidal surgery. An hypertensive hemorrhagic cyst was found with no tumor. The second patient had acromegaly. While performing a LHRH-stimulation test he had an ictus of headache, vomiting, no visual loss and appearance of diabetes insipidus. A CT scan disclosed an intrasellar hematoma. Despite the size of the tumor and since there was no visual impairment, this patient was followed up without surgery. Imaging follow-up showed a progressive shrinkage and disappearance of the mass, which was corroborated by endocrine remission. A high rate of recurrence is reported in such patients in the literature. Both patients are being currently followed-up on a long-term basis.
Magnetic resonance imaging of cavernous sinus invasion by pituitary adenoma diagnostic criteria and surgical findings
Ressonância magnética da invasão do seio cavernoso por adenomas hipofisários, critérios diagnósticos e achados cirúrgicos
Joaquim O. Vieira Jr. II; Arthur Cukiert II; Bernardo Liberman I
Hospital Brigadeiro, São Paulo SP, Brazil
I – Department of Endocrinology
II – Department of Neurosurgery
This study used MRI to define preoperative imaging criteria for cavernous sinus invasion (CSI) by pituitary adenoma (PA). MR images of 103 patients with PA submitted to surgery (48 with CSI) were retrospectively reviewed. The following MR signs were studied and compared to intraoperative findings (the latter were considered the gold standard for CSI detection): presence of normal pituitary gland between the adenoma and CS, status of the CS venous compartments, CS size, CS lateral wall bulging, displacement of the intracavernous internal carotid artery (ICA) by adenoma, grade of parasellar extension (Knosp-Steiner classification) and percentage of intracavernous ICA encased by the tumor. Statistical analysis was performed using qui-square testing and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were obtained for each MR finding. The following signs have been found to represent accurate criteria for non-invasion of the CS: 1- normal pituitary gland interposed between the adenoma and the CS (PPV, 100%); 2- intact medial venous compartment (PPV, 100%); 3- percentage of encasement of the intracavernous ICA lower than 25% (NPV, 100%) and 4- medial intercarotid line not crossed by the tumor (NPV, 100%). Criteria for CSI were: 1- percentage of encasement of the intracavernous ICA higher than 45%; 2- occlusion of three or more CS venous compartments and 3- occlusion of the CS lateral venous compartment. The CS was very likely to be invaded if the inferior venous compartment was not detected (PPV. 92,8%), if the lateral intercarotid line was crossed (PPV. 96,1%) or if a bulging lateral dural wall of the CS was seen (PPV, 92,3%). The preoperative diagnosis of CSI by PA is extremely important since endocrinological remission is rarely obtained after microsurgery alone in patients with invasive tumors. The above mentioned MR imaging criteria may be useful in advising most of the patients preoperatively on the potential need for complimentary therapy after surgery.
Este estudo utilizou exames de RM para definir critérios pré-operatórios de imagem para invasão do seio cavernoso (ISC) em adenomas hipofisários (AH). As imagens de RM de 103 pacientes com AH tratados cirurgicamente (48 com ISC) foram revisadas retrospectivamente. Os seguintes sinais de RM foram estudados e comparados aos achados intraoperatórios (considerados o padrão-ouro para invasão do seio cavernoso): presença de glândula hipofisária normal interposta entre o adenoma e o SC, situação dos compartimentos venosos do SC, tamanho do SC, abaulamento da parede lateral do SC, deslocamento da artéria carótida interna (ACI) intracavernosa pelo adenoma, grau de extensão paraselar (classificação de Knosp-Steiner) e porcentagem de envolvimento da ACI intracavernosa pelo tumor. A análise estatística foi realizada utilizando o teste de qui-quadrado e a sensibilidade, especificidade, valor preditivo positivo (VPP) e valor preditivo negativo (VPN) foram obtidos para cada critério de imagem. Os seguintes sinais representaram critérios precisos de ausência de invasão do SC: 1- presença de glândula hipofisária normal interposta (VPP de 100%); 2-compartimento venoso medial visível (VPP de 100%); 3-porcentagem de envolvimento da ACI intracavernosa inferior a 25% (VPN de 100%); 4-não cruzamento da linha intercarotídea medial pelo tumor (VPN de 100%). Os critérios definidos para invasão do SC foram: 1-porcentagem de envolvimento da ACI intracavernosa maior que 45%; 2-não visualização de 3 ou mais compartimentos venosos do SC; 3-não visualização do compartimento venoso lateral do SC. A presença de invasão do SC era muito sugestiva quando o compartimento venoso inferior não era visível (VPP de 92,8%), a linha intercarotídea lateral era cruzada (VPP de 96,1%) ou quando a parede lateral do seio cavernoso estava abaulada (VPP de 92,3%). O diagnóstico pré-operatório de ISC por adenomas hipofisários é extremamente importante, pois a remissão endócrina é raramente obtida em pacientes com tumores invasivos tratados apenas por microcirurgia. Os critérios de imagem acima mencionados podem ser úteis para alertar a maioria dos pacientes no pré-operatório da necessidade potencial de tratamento complementar adjuvante após a cirurgia.
Pituitary adenomas (PA) are benign tumors, which usually grow causing compression of adjacent anatomical structures and sellar enlargement. However, some PA may infiltrate adjacent tissues, such as the sphenoid sinus, diaphragma sellae and cavernous sinus (CS). These adenomas have a more aggressive biological behavior and are considered to be invasive. Ten percent of PA invades the CS1,2. The surgical morbidity and mortality might be increased in these patients and tumor resection is usually partial, yielding a low rate of endocrinological remission. Adjuvant treatment (radiotherapy or medication) is often necessary in these patients. The preoperative diagnosis of cavernous sinus invasion (CSI) is important in the planning of surgical and adjuvant treatment strategies.
The clinical signs of CSI occur only late in time, so that its precocious diagnosis can only be performed through imaging. MRI is the best technique to evaluate the sellar region, but it is not always accurate to precisely demonstrate the CS/pituitary interface. Total encasement of the internal carotid artery (ICA) by the tumor has been classically defined as a sign of invasion on MRI, but this also occur only late during tumor progression. The diagnosis of CSI is usually performed at surgery. Experienced neurosurgeons can easily distinguish between normal and abnormal dural walls. Some authors1-6 have tried to define imaging criteria for CSI using anatomical parameters, such as the intracavernous ICA and the CS venous compartments; they have also compared imaging and surgical findings.
The purpose of this paper was to investigate MRI criteria that could potentially provide reliable preoperative information on the presence of CSI.
Clinical data related to the endocrinological syndrome, the presence or not of headache and surgical outcome were available for all patients. MRI findings of 103 patients (62 women, 41 man; age ranging from 13 to 75 years) with PA who underwent surgical treatment at Hospital Brigadeiro from March 1992 to August 2002 were retrospectively reviewed.
There were 47(45.5%) patients with acromegaly, 36 (35.0%) with Cushing’s disease, 14(13.5%) with nonsecreting tumors, 3(3.0%) with prolactinoma, 2(2.0%) with gigantism and 1(1.0%) with TSH secreting adenoma.
All patients have MR examinations performed on 1.5T units. We analyzed gadolinium enhanced coronal images, obtained through T1-weighted spin-echo sequences with TR=500 and TE=20, a 192×256 acquisition matrix, a 20 cm field of view and 3 mm thick slices.
Two observers who had no knowledge of the surgical findings jointly analyzed the MR images. PA were classified by size in micro (<10mm) or macroadenomas (>10mm). CS spaces were divided into 4 venous compartments as related to the ICA, as previously described7: the medial compartment, which is located between the ICA and pituitary fossa; the superior compartment, which is above the ICA; the lateral compartment, which is lateral to the ICA and the inferior compartment, which is under the ICA. The parasellar extension of the tumors was classified according the Knosp-Steiner classification1: grade 0, when the adenoma did not cross the medial intercarotid line; grade 1, when the tumor passed the medial intercarotid line but did not cross the median intercarotid line; grade 2, when the tumor passed the median intercarotid line but did not cross the lateral intercarotid line; grade 3, when the adenoma passed the lateral intercarotid line and grade 4, when the ICA was totally encased by the tumor. The observers evaluated the following MRI features: 1. presence of normal pituitary gland between the adenoma and CS; 2. status of the CS venous compartments; 3. CS size; 4. CS lateral wall bulging; 5. displacement of the intracavernous ICA by the adenoma; 6. grade of parasellar extension (Knosp-Steiner classification1); 7. percentage of the intracavernous ICA encased by the tumor, which was calculated measuring the angle of the artery’s perimeter invaded by the tumor, using digital tools (Fig 1).
All patients underwent surgical treatment (99 patients through a transesphenoidal approach and 4 through craniotomy) by experienced neurosurgeons. The surgical findings were considered the gold standard for CSI. At surgery, invasion was defined by the direct observation through the surgical microscope of perforation of the medial wall of the CS or clear-cut CS dural involvement by the tumor. The presence of invasion of the duramater of the sellar floor and the extent of tumor resection (partial or total) were also documented. The majority of the procedures were recorded on tape.
MR and surgical findings were compared using c2 testing. P<0.05 values were considered statistically significant. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each criterion. The criteria with best results in c2 testing were evaluated together by forward stepwise selection and the significant criteria (p<0.01) were used to elaborate a predictive score of CS invasion. The probabilities of CSI were obtained with the significant criteria by the multiple logistic regression equation (Y=b0 + b1.X1 + b2.X2).
The results of surgical morbidity and outcome were compared in patients with or without CSI or sellar floor’s duramater involvement. The median follow-up time was 46 months (range 4 to 149 months).
This study was approved by the Hospital Brigadeiro Ethics Committee.
Fifty-one (25%) of the 206 CS (103 patients) were unequivocally invaded by PA at surgery. The invasion was unilateral in 45 patients (23 at right side and 22 at left side) and bilateral in 3.
Among the 48 adenomas with CSI, 8 were microadenomas (16.5%) and 40 macroadenomas (83.5%). Twenty-two of the 55 adenomas without invasion were microadenomas (40.0%) and 33 macroadenomas (60.0%). This association was statistically significant (p<0.009).
Complete surgical removal of the tumor was performed in 13 (27.0%) of the 48 patients with CSI and partial resection in 35 cases (73.0%). In noninvasive adenoma, total tumor resection was obtained in 47 patients (85.5%) and partial removal in 8 (15.5%) (p<0.001).
Follow-up data were available in 98 patients (55 with CS and sellar floor dural invasion and 43 without invasion). Ten patients (18.0%) have been cured by surgical treatment within the invasive group; the remaining 45 patients (82.0%) required adjuvant treatment (radiotherapy in 37 patients and suppressive drug therapy in 24). In the group with non-invasive tumors, 27 patients (63.0%) have been cured by surgery alone and 16 (37.0%) required adjuvant therapy (radiotherapy in 11 patients, suppressive drug therapy in 8 and adrenalectomy in 1) (p<0.001).
Headache was present in 25 patients (41,5%) with dural invasion (CS and sellar floor) and in 24 (56.0%) patients with non-invasive tumors (not statistically significant).
All the CS in which the medial venous compartment was visualized or there was normal pituitary gland interposed between the tumor and the CS were not invaded by the lesion (PPV, 100.0%) (p<0.001).
None of the patients with parasellar extension grade 0 had CSI. On the other hand, all patients with parasellar extension grade 4 had CSI (PPV.100%). The summary of the results regarding parasellar extension can be seen in Table 1.
Displacement of the intracavernous ICA, bulging of the CS lateral wall and an increase in size of the CS were found to be associated with invasion (p<0.001), although only CS lateral wall bulging demonstrated a good PPV (92.3%).
The medial venous compartment was not depicted in all invaded CS (100.0% sensitivity and NPV, p<0.001) and in 54 CS without invasion. This compartment was depicted in the remaining 101 CS without invasion. Non-visualization of the inferior and lateral venous compartments had the highest positive predictive values (92.8% and 100.0%, respectively; p<0.001). The results regarding visualization of the different CS venous compartments are summarized in Table 2.
The CS was always invaded when 3 or more venous compartments were not visualized (PPV 100%, p<0.001).
CS was never invaded when the percentage of encasement of the ICA was lower than 25% (NPV 100%, p<0.001). On the other hand, when more then 45% of the circumference of the intracavernous ICA was involved by the adenoma, all CS were invaded (PPV 100%, p<0.001) (Table 3).
The criteria with stronger association with CSI by c2 testing were: a) increase of CS size, b) bulging of CS lateral wall, c) displacement of the intracavernous ICA, d) parasellar extension grade 2 or more, e) non depiction of the superior or inferior venous compartment, f) 2 or more venous compartment not visualized and g) ICA encasement> 30%. Comparing all these criteria together, only 3 were statistically significant alone: 2 or more venous compartment not visualized, non depiction of the inferior venous compartment and ICA encasement > 30% (Table 4).
For each of these 3 selected criteria a value weighted by its significance were chosen to make the predictive score of CSI (Table 5). This predictive score ranged from 0 to 6. A total score greater than 2 had the best diagnostic value for CSI (sensitivity 94.1%, specificity 92.9%).
The presence of CSI by PA is clinically relevant. Surgical procedures might be more difficult and tumor resection is usually partial in patients with invasive tumors. This yields poorer endocrinological results and adjuvant treatment (radiotherapy, medical suppressive drugs or adrenalectomy) is often necessary. Only 18.0% of the patients in our series with CS and sellar floor dural invasion have been cured by surgery alone. Radiotherapy was performed in 67.0% of the patients with invasive adenomas and drug therapy in 43.5%. The surgical resection was complete in 85.5% of the patients with non-invasive tumors. Sixty-three percent of them have been cured by surgery alone; 25.5% of the patients needed radiotherapy and 18.5% drug therapy. Although preoperative diagnosis of CSI has a major impact on surgical outcome, only a few papers have specifically discussed the issue.
The absence of a bony interface in the lateral limits of the pituitary fossa might explain why tumor extension to the parasellar region and invasion of the CS are relatively common. A dural bag limited laterally by venous spaces within the CS surrounds the pituitary gland. There is only a thin dural layer between the gland and CS, which is called the medial wall. In about 30% of normal individuals, the pituitary gland has a lateral expansion reaching the intracavernous ICA, but the encasement of the ICA by the gland is always less than 25%8. Laterally invading tumors have to be distinguished from these lateral normal pituitary expansions.
Intraoperative findings were considered the gold standard for CSI in our study. This is possibly the best single objective available criterion, but it is highly dependent on the surgeon’s personal expe rience and it has to be recognized that in some patients it is very difficult to adequately visualize the lateral aspects of the pituitary fossa.
MRI is superior to CT scanning in defining the pituitary gland and the sellar region and its boundaries. On the other hand, both techniques do not adequately depict the medial wall of the CS4,9-13.
The prevalence of CSI in our series is probably overestimated (46.5% of the patients). The present series did not include all the patients with PA treated at our institution. Intervening patients were excluded due to non-availability of adequate MRI images for analysis, lack of full clinical or follow-up data or lack of unequivocal intraoperative information regarding invasion or not by the tumor. CSI occurs more often unilaterally. In Scotti et al.4 and Cottier et al.2 series, invasion by PA occurred only unilaterally. In our series, unilateral invasion by PA was observed in 93.7% of the patients and bilateral invasion occurred in 3 patients (all with GH-secreting adenoma). Knosp et al.1 observed bilateral invasion in 3 patients from their series (all with nonfunctioning PA).
We observed a significantly increased prevalence of invasion in macroadenomas (83.5% of the patients with invasive tumors). This higher prevalence of invasive tumors has also been observed by others1-3,5, although Scotti et al.4 have not noticed such difference. Knosp et al.1 have also noted that the grade of parasellar extension was directly related to the tumor’s size. Selman et al.14 have demonstrated histologically that dural invasion in adenoma was well correlated to the tumor’s size.
Headache is a frequent symptom in PA, but its pathogenesis is not well understood. Arafah et al.15 observed that patients with PA and headache had increased intrasellar pressure compared to those without headache. In our series, we found no correlation between the presence of dural invasion by the tumor and headache.
We were able to define 4 MR criteria for the absence of CSI in patients with PA: 1- normal pituitary gland interposed between the tumor and the CS; 2-intact CS medial venous compartment; 3- tumor not crossing the medial intercarotid line and 4- percentage of ICA encasement by the lesion lower than 25%.
Cottier et al.2 also considered the presence of normal pituitary gland interposed between the tumor and the CS and intact CS medial venous compartment as seen on MRI as criteria for absence of CSI. Moreau et al.5 also observed that there was no actual tumor invasion when the lesion did not cross the medial intercarotid line. Despite high specificity (100,0%), the 3 criteria above for absence of CSI had a very low sensitivity. ICA encasement lower then 25% disclosed the highest specificity (100,0%) and sensitivity (83,0%) for absence of CSI.
Other criteria highly suggestive of absence of CSI in our study were intact superior venous compartment (NPV, 92.4%) and the visualization of at least 3 CS venous compartments (NPV, 96%). Cottier et al.2 noted that besides the visualization of an intact CS superior venous compartment, the absence of size asymmetry between the 2 CS, absence of bulging of lateral wall of CS and grade 2 or less of parasellar extension were also good signs of absence of CSI. In the study of Moreau et al5, the signs highly suggestive of absence of invasion were lack of size asymmetry, lack of bulging of the lateral wall of the CS, visualization of at least two venous compartments and non-displaced ICA.
The displacement of ICA and CS size asymmetry were shown to be criteria with good specificity but low sensitivity and PPV for CSI in our series. Cottier et al.2 obtained similar results for these criteria.
Bulging of the lateral wall of the CS had a good specificity and PPV but low sensitivity in our series. These findings were in disagreement with Cottier’s et al.2 data which disclosed a very low PPV.
In our study, we observed that in patients with Knosp parasellar extension grade 3 the CS was probably invaded (VPP, 96.1%) and with grade 4 (total ICA encasement), it was certainly invaded. However, the sensitivity for these criteria was very low. Cottier et al.2 and Moreau et al.5 also observed that CSI was very likely when the lateral intercarotid line was crossed by the tumor. However, Knosp et al.1 noted that adenoma with grade 2 or higher always had CSI. Their series evaluated only patients with CSI.
The non-visualization of the inferior or lateral CS venous compartments was very suggestive of CSI (PPV, 92.8% and 100% respectively). CSI was always present when 3 or more CS venous compartments were not depicted on MRI (PPV, 100%). Cottier et al2 further divided the CS inferior venous compartment into carotid sulcus and inferolateral compartments, and observed that non-visualization of the carotid sulcus venous compartment had a high PPV (95.0%) for CSI. However, contrary to our results, these authors did not observe good PPV for invasion when the CS lateral venous compartment was not seen.
Total encasement of ICA by adenoma (grade 4 of Knosp1) definitely indicated CSI (PPV and specificity of 100%) in our series, but it had low sensitivity and occurred late in time. In our series, only 13.7% of the CSI showed total encasement of ICA. Knosp et al.1 observed this sign in 32.0% of the invaded CS and Cottier et al.2 in 24.0%.
Adenoma grows progressively around the ICA after infiltrating the CS medial wall. Moreau et al.5 observed that in patients in whom there was 25% or more of ICA encasement by the tumor CSI was very likely. In our study, we observed that ICA encasement higher then 45% was always associated with CSI (PPV, 100%). Cottier et al.2suggested that at least 67% of ICA encasement would be needed to assure CSI.
Comparing statistically the significant criteria all together, only 3 had separately association with CSI: 2 or more venous compartment not visualized, non depiction of the inferior venous compartment and ICA encasement >30%. With these criteria, we proposed a practical predictive score for CSI to make its preoperative diagnosis easier.
Our data showed that accurate analysis of MR findings is useful in the preoperative diagnosis of CSI by PA and is able to generate relevant information regarding the microsurgical outcome in this patient’s population. The most specific and precocious sign of invasion was the encasement of the intracavernous ICA greater than 45%; when ICA encasement was lower than 25% the CS was never invaded. CS was definitely invaded when the lateral venous compartment was not visualized or when three or more venous compartments were not depicted. CS was never invaded when the medial venous compartment was intact or normal pituitary gland was interposed between the adenoma and the CS.
The most useful sign to predict CSI was the encasement of ICA greater than 30%. This precocious finding had the best sensitivity (92.1%), specificity (93.5%) and PPV (82.5%).
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- Nichols DA, Laws ER Jr, Houser OW, Abboud CF. Comparison of magnetic resonance imaging and computed tomography in the preoperative evaluation of pituitary adenomas. Neurosurgery 1988;22:380-385.
- Selman WR, Laws ER Jr, Scheithauer BW, Carpenter SM. The ocurrence of dural invasion in pituitary adenomas. J Neurosurg 1996;64:402-407.
- Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J. Clin. Endocrinol. Metab. 2000;85:1789-1793.
Intrasellar internal carotid aneurysm coexisting with GH-secreting pituitary adenoma in an acromegalic patient
Aneurisma intraselar da carótida interna coexistindo com adenoma secretor de GH em paciente acromegálico
Lauro Seda Jr I; Arthur Cukiert I; Kátia C. Nogueira II; Martha K.P. Huayllas II; Bernardo Liberman II
I – Departments of Neurosurgery, Hospital Brigadeiro and Clínica Neuroendócrina de São Paulo, São Paulo SP, Brazil
II – Departments of Endocrinology, Hospital Brigadeiro and Clínica Neuroendócrina de São Paulo, São Paulo SP, Brazil
The coexistence of pituitary adenoma and cerebral aneurysm is rare, although its prevalence is higher then would be expected in general population1-5. We report on an extremely rare condition where growth hormone (GH) -secreting adenoma coexisted with an intrasellar internal carotid artery (ICA) aneurysm.
A 58 years old female presented with headache and acromegalic phenotype. She had hypertension for 10 years and galactorrhea for 3 years. Mean plasma GH was 8.1 hg/mL and mean IGF-1 level was 703 hg/mL (Reference: 78–258 hg/mL by immunoradiometric assay). Results obtained during pre- and postoperative glucose tolerance tests (OGTT) and octreotide response test (100 mg administered subcutaneously every six hours) can be seen in Table 1 and 2, respectively. Prolactin baseline level was 28.6 ;hg/mL and pituitary function was otherwise intact. Magnetic resonance imaging (MRI) of the sellar region disclosed a 1.2 cm ICA aneurysm occupying the left hemisella and a 0.7 cm pituitary adenoma just bellow it (Fig 1A). Angiography disclosed left ICA aneurysm posterior to the emergency of the ophthalmic artery (Fig 1B). The patient tolerated well a balloon occlusion test and was submitted to aneurysm exclusion through ICA occlusion in the neck and transcranial clipping of the supraclinoid ICA immediately below the ophthalmic artery’s exit. One month afterwards, she was submitted to complete adenoma removal through a transsphenoidal approach (Fig 2). The excluded aneurysm was easily seen occupying the entire left hemisella. Immunohistochemical examination confirmed the presence of GH-secreting adenoma. Immediate postoperative GH and prolactin levels were 3.7 and 5.6 hg/mL, respectively. Four days later, IGF-1 was 543 hg/mL (78–258 hg/mL). One month after adenoma removal, GH and IGF1 levels were 5.0 hg/mL and 527 hg/mL, respectively. After 3 months of follow-up, patient’s GH and IGF-1 levels were 4.1 hg/mL and 413hg/mL, respectively. It was not possible to perform a follow-up MRI since the clip used in surgery was not MRI-compatible.
She was then started on Sandostatin® LAR 30 mg / month. Four months later, IGF-1 and GH levels were 107hg/mL (Reference: 81–225 hg/mL) and 0.9 hg/mL, respectively. By this time, patient underwent radiosurgery. After two years of follow-up, the patient remained in remussion and receiving Sandostatin LAR.
This case report was agreed by the local ethic committee.
The prevalence of sellar-region’s aneurysm among others is 1-2%2. The prevalence of the coexistence of pituitary adenoma and cerebral aneurysm is higher then that with other benign brain tumors in the general population5. Approximately 50% of these patients have acromegaly1,3,5-8, suggesting that high GH and IGF-1 levels or their biological effects might be implicated in the aneurysm’s genesis. High IGF-1 induces artery dilation8, atherosclerotic and degenerative changes of the artery wall8,9, tumor invasion and tumor-directed neovessels9. Hypertension and diabetes are very likely to be involved in the process5. Patients with intrasellar (not intracranial) aneurysms and pituitary adenomas are extremely rare.
Mostly, the diagnosis of such aneurysms is incidental, and occurs when performing the preoperative investigation for adenomas7. However, different clinical presentations may occur, such as fatal epistaxis10 or pituitary apoplexy11 , as a result of aneurismal bleeding into the adenoma. Misdiagnosis of this condition may have hazardous hemorrhagic consequences.
These two conditions must be treated. Although simultaneous microsurgical treatment of the aneurysm and the adenoma through a pterional or a supraorbital keyhole approach has been advocated in different reports6,12,13, approaching the vascular lesion first is usually the best choice. In our case, we performed an ICA entrapment by endovascular occlusion in the neck and transcranial clipping of ICA just bellow the ophthalmic artery’s emergence. This treatment was possible because the patient tolerated well a previous balloon occlusion test. One month later, the adenoma was completely removed through a transsphenoidal route. Nevertheless, the patient did not achieved endocrinological remission and needed adjuvant therapy with Octreotide and radiosurgery. Clinical and endocrinological control were then obtained.Although the results obtained while treating this patient were good, a minimally invasive therapeutic option would also be available for such patients: the vascular lesion could be treated by endovascular trapping of the internal carotid artery and the GH-secreting tumor could have been treated primarily with somatostatin analogs or transsphenoidal surgery. Primary clinical treatment with somatostatin should be considered especially in patients with known cavernous sinus invasion by the tumor and no mass effect directed to the optic apparatus14-15.
We believe that the treatment of this dual-pathology should be carried out in two steps: vascular pathology should be treated first to avoid potential future catastrophic hemorrhage and the pituitary pathology afterwards.
- Jakubowski J, Kendall B. Coincidental aneurysms with tumors of pituitary origin. J Neurol Neurosurg Psychiatry 1978;41:972-979.
- Acqui M, Ferrante L, Fraioli B. Association between intracranial aneurysms and pituitary adenomas: etiopathogenic hypotheses. Neurochirurgia 1987;30:177-181.
- Pant B, Arita K, Kurisu K. Incidence of intracranial aneurysms associated with pituitary adenoma. Neurosurg Rev 1997;20:13-17.
- Heshmati HM, Fatourechi V, Dagam SA, Piepgras DG. Hypopituitarism caused by intrasellar aneurysms. Mayo Clin Proc 2001;76:789-793.
- Wakai S, Fukushima T, Furihata T. Association of cerebral aneurysm with pituitary adenoma. Surg Neurol 1979;12:503-507.
- Hori T, Muraoka K Hokama Y. A growth-hormone producing pituitary adenoma and an internal carotid artery aneurysm. Surg Neurol 1982;18: 108-111.
- Sade B, Mohr G, Tampieri D, Rizzo A. Intrasellar aneurysm and a growth hormone-secreting pituitary macroadenoma. J Neurosurg 2004; 100:557-559.
- Weir B. Pituitary tumors and aneurysms case report and review of the literature. Neurosurgery 1992;30:585-591.
- Mangiardi JR, Aleksic SN, Lifshitz M. Coincidental pituitary adenoma and cerebral aneurysm with pathological findings. Surg Neurol 1983;19: 38-41.
- Imamura J, Okuzono T, Okuzono Y. Fatal epistaxis caused by rupture of an intratumoral aneurysm enclosed by a large prolactinoma: case report. Neurol Med Chir 1998;38:654-656
- Suzuki H, Muramatsu M, Murao K. Pituitary apoplexy caused by ruptured internal carotid aneurysm. Stroke 2001;32:567-569.
- Fujiwara S, Fujii K, Nishio S. Diagnosis and treatment of pituitary adenoma with adjacent carotid artery aneurysm. J Neurosurg Sci 1991;35: 41-46.
- Revuelta R, Arraiada-Mendicoa N, Ramirez-Alba J. Simultaneous treatment of a pituitary adenoma and an internal carotid artery aneurysm through a supraorbital keyhole approach. Minim Invasive Neurosurg 2002;45:109-111.
- Vieira JO, Cukiert A, Liberman B. Evaluation of MRI criteria for cavernous sinus invasion in patients with pituitary adenoma: logistic regression analysis and correlation with surgical findings. Surg Neurol 2006;65:130-135.
- Vieira JO, Cukiert A, Liberman B. MRI of cavernous sinus invasion by pituitary adenoma: diagnostic criteria and surgical findings. Arq Neuropsiquiatr 2004;62:437-443.
Pinheiro MM1, Liberman B, Salgado LR, Goldman J, Nery M, Cukiert A.
Cushing’s disease is rare in children and its occurrence in identical twins is extremely rare. This paper reports on identical twins discordant for Cushing’s disease. One of them first presented with a cushingoid phenotype by the age of 10. Her evaluation showed an increased urinary free-cortisol and serum ACTH. Her pattern in the dexametazone suppression tests was compatible with Cushing’s disease. MRI disclosed a pituitary macroadenoma which was removed by the transesphenoidal approach. Immunohistochemical studies of the tumor showed the presence of ACTH-producing cells. The patient went into clinical and laboratorial remission after surgery. She re-started to grow after the disappearance of the Cushing’s phenotype but she is still shorter than her healthy sister. The latter remains disease-free 4 years after her sister’s diagnosis. This represents the third such case reported in the literature. Our findings suggest that acquired factors may be responsible for the genesis of Cushing’s disease.
hCG-secreting pineal teratoma causing precocious puberty: report of two patients and review of the literature
Nogueira K1, Liberman B, Pimentel-Filho FR, Goldman J, Silva ME, Vieira JO, Buratini JA, Cukiert A.
Two boys are described with precocious puberty (PP) due to pineal immature teratoma associated with choriocarcinoma. Patient 1 was a 7 year-old boy with a 2-year history of PP. He had elevated CSF and plasma beta-hCG levels. Magnetic resonance imaging (MRI) showed a 3.0 cm pineal mass. He was initially submitted to a trial with radiotherapy, followed by radical surgical resection, stereotactic radiotherapy and chemotherapy. Long-term follow up included the appearance of acute hydrocephalus requiring CSF shunting, local hemorrhage and extensive radionecrosis. Death occurred 1.5 years after diagnosis. Patient 2 was a 7 year-old boy with an 8-month history of PP. He had elevated CSF and plasma beta-hCG and alpha-fetoprotein levels. MRI showed a 1.0 cm pineal mass. He was submitted to radical surgical resection (which caused normalization of levels of markers) and prophylactic chemotherapy. The boy is doing well 1.5 years after diagnosis. An extensive review of the literature corroborates the idea that this last treatment paradigm (surgery and chemotherapy) probably represents the best treatment regimen for these patients.