The studies of melatonin values in the cerebrospinal fluid of hydrocephalic patients

The changes in daytime levels of melatonin (MLT) in the cerebrospinal fluid (CSF) of twenty seven hydrocephalic patients were studied by the high-performance liquid chromatography (HPLC) method. Patients comprised three with congenital hydrocephalus (spina bifida 1, Chiari type II malformation 2), four post-meningitic hydrocephalus, fifteen brain tumors (chiasmal germinoma 3; malignant glioma of frontal 3, and temporal lobes 1; germinoma 1, teratoma 2, yolk sac tumor 1, epidermoid 1 in pineal region) and five cases of normal pressure hydrocephalus. CSF was collected between 0930 and 1030 h through puncture of the flushing device of shunt system or the lateral ventricle. The lowest value of MLT detected by HPLC was 15 pg/ml. Melatonin values were higher in patients aged under 10 years than over 20 years in the absence of meningitis or tumor in the pineal region. Even at ages over 15 years, higher CSF MLT values were obtained in the patients with meningitis or tumors in the pineal region. These results suggest that the inflammation or invasion of tumor into the pineal gland may stimulate the secretion of MLT by the pineal gland. However, lower MLT values were obtained in all patients over 40 years old. For these reasons, if one may use the changes of MLT values in CSF as a tumor marker or for determination of the treatment modality, time of CSF collection, age of patient, location or character of the tumor and presence of meningitis should be given due consideration. Also, the presence or absence of the rhythmical changes of melatonin values in a day following circadian rhythm are very important in determination of the treatment modality.     

Primary intrasellar mixed germ-cell tumor with precocious puberty and diabetes insipidus

We report an 8-year-old boy with a primary intrasellar mixed germ-cell tumor who underwent the trans-sphenoidal approach for tumor removal. Initially he suffered from diabetes insipidus. Precocious puberty and left abducens nerve palsy were also observed. Elevation of serum testosterone, β-human chorionic gonadotropin (HCG), and α-fetoprotein (AFP) were found on admission. The histological study revealed mixed cellular types of tumor including germinoma, choriocarcinoma, embryonic cell carcinoma, and teratoma. Postoperative radiation to a total of 5000 cGy was performed. Adjuvant chemotherapy was administered before and after radiation. The boy was disease-free during a 6-month follow-up period. Follow-up magnetic resonance imaging showed no presence of tumor. The signs of precocious puberty disappeared, and the diabetes insipidus was easily controlled. The abducens nerve regained normal function. Serum HCG, AFP, and testosterone levels all returned to normal. Serum anti-diuretic hormone increased to reach the lower limit of the normal range. Received: 27 March 1995     

Teratoma of the 4th ventricle and precocious puberty. Case report]

A case of precocious puberty and diabetes insipidus in a 7 years old boy due to a malignant teratoma in the IVth ventricle is reported. The tumor had grown into the IIIrd and lateral ventricles as found on the necropsy. The original site of the tumor and the possible physiopathological mechanisms for the precocious puberty are discussed.     

Germ cell tumors of the thalamus and the basal ganglia

Two cases of germ cell tumors (GCTs) of the basal ganglia are presented and 40 previously reported cases are reviewed. The incidence of GCTs of the basal ganglia and thalamus was estimated as less than 14% of all intracranial GCTs. All patients except for two (95%) were male, aged 7–19 years. The clinical course was usually slow. The major symptoms were hemiparesis, mental deterioration such as dementia or character change, precocious puberty, diabetes insipidus, oculomotor palsy, speech disturbance, and hemianopsia. Signs of intracranial hypertension did not occur until the late stages of the disease. The plain CT finding was characterized by an irregularly defined, slightly high-density area frequently accompanied by central low-density areas without significant mass effect. The tumors showed mild to moderate and nonhomogeneous contrast enhancement. An ipsilateral cerebral hemiatrophy was often found. MR images demonstrated the corresponding findings. GCTs of the basal ganglia had a high possibility of containing components other than germinoma such as choriocarcinoma, endodermal sinus tumor, and embryonal carcinoma. Thus, tumor markers in the serum, CSF, or cyst fluid were frequently positive. With recent refinement of microsurgical techniques as well as immunohistochemical study and measurements of tumor markers of serum, CSF, and cyst fluid, major resections of tumor, accurate pretreatment histologic diagnosis, and early determination of the specific types of this tumor appear to be readily possible. This is essential for effective treatment of patients not only with radiosensitive germinoma, but also those with radioinsensitive nongerminoma variants and a combination of them located in this region.     

原发性松果体区胚胎癌的诊断与治疗(附二例报告及文献复习)

目的 原发性松果体区胚胎癌非常罕见,本文报道2例,并结合文献探讨其诊断、治疗和预后.方法 2例经病理证实的原发性松果体区胚胎癌,术前例1患者血清甲胎蛋白(AFP)6 810μg/L,人绒毛膜促性腺激素(β-HCG)正常,例2患者血清AFP正常,β-HCG 5 260 mIU/ml.采用枕部经小脑幕入路显微手术切除肿瘤,术后联合放化疗.结果 2例患者肿瘤均达到镜下全切,术后肿瘤免疫组化示例1:CK、AFP阳性;例2:CK、β-HCG阳性.经放化疗后,血清AFP/β-HCG基本正常.术后1年随访2例患者仍然存活.结论 血清AFP、β-HCG对胚胎癌的诊断及预后判断有重要作用,免疫组化指标CK、AFP、β-HCG对病理诊断有鉴别意义,该病采用手术联合放化疗的综合疗法,可获得较好疗效.

Abstract：

Objective Primary embryonal carcinoma in pineal region is extremely rare Here we report two such cases and combined literatures review to discuss its diagnosis, treatment and prognosis. Method Two primary embryonal carcinoma in pineal region verified histologically were presented. In one cases, the preoperative serum alpha - fetoprotein (AFP) level reached significantly high level, 6 810μg/L, but showed negative staining forβ-human chorionic gonadotropin (β- HCG) . In the other one, accompanied by elevation of β-HCG level, 5 260 mIU/ml, the serum AFP was negative. The tumors were microsurgically removed by transeccipito-tentorial approach. Endoscopic third ventriculostomy was used after tumor removal because of recurrent hydrocephalus. Both patients received adjunctive treatments included radiation therapy (whole central nervous system 30 Gy and tumor bed 50 Gy) and 4 course of chemotherapy. Results In both patients, the tumors were totally removed. Postoperative tumor immunohistochemistry indicators were present in case 1 with positive reaction for cytokeratin(CK) and AFP, in case 2 with positive CK and β - HCG. After adjunctive treatments, the serum AFP and β - HCG of two patiants were decreased to normal ranges. After post - operative follow - up of one year,two patients still survived and the serum markers were almost normal. Conclusions Measurement of serum β-HCG and AFP is extraordinarily significant for the diagnosis and post - treatment monitoring of pineal region embryonal carcinoma. Pathological differential diagnosis requires immunohistochemical indicators including cytokeratin (CK),AFP andβ- HCG. With radically surgical removal and combined adjunctive therapy including radiation and chemotherapy, good consequence could be obtained.     

Diurnal variation in glucose utilization in the pineal body of the monkey

We employed the quantitative 2-[14C]-deoxyglucose method (Sokoloff's method) to measure glucose utilization in the pineal gland of pubescent monkeys. Glucose utilization in the pineal was 80-110% higher in the nocturnal, awake animals compared to the rate of both groups studied in the nocturnal, awake animals with both eyes open and with light deprivation for three hours. Short term visual deprivation during the day was without effect on pineal glucose utilization. The diurnal variations in melatonin levels in blood and CSF, higher at night than during the day, are the result of corresponding changes in the rate of production and elaboration of melatonin in the pineal gland. The release of norepinephrine from the postganglionic fiber of the superior cervical ganglia controls the production of melatonin in the pineal by regulating the activity of serotonin-N-acetyltransferase. It was reported that electrical stimulation of SCG via sympathetic trunk increased the levels of serotonin-N-acetyltransferase in the pineal and that it also increased glucose utilization in the pineal. It is believed that metabolic increase in the pineal reflects increased activity in sympathetic terminals distributed throughout the gland which stimulate its increase in hormone production. The present results indicate that there is an elevation of pineal metabolic rate at a time when blood and CSF levels of melatonin are known to be elevated Our finding that short-term light deprivation during the day did not affect the pineal metabolic rate is consistent with the result by Reppert et al (1981) in which they found that exposure to darkness during the day does not result in an increase in CSF melatonin.     

松果体区肿瘤致男性性早熟8例临床分析

目的探讨男性松果体区肿瘤患儿性早熟的原因和临床特征。方法对8例有性早熟表现的男性松果体区肿瘤患儿的临床资料进行回顾性分析,并在肿瘤病理和生殖细胞肿瘤标志物方面与11例无性早熟表现的患儿进行比较。结果本组8例性早熟患儿占同时期、同年龄段男性松果体区肿瘤患儿的42%。3例性早熟为首发表现,5例为临床表现之一。性早熟多早于其它症状出现,但常被忽视。性早熟患儿的松果体区肿瘤均为恶性生殖细胞肿瘤,且均能分泌β-人绒毛膜促性腺激素（β-HCG）。结论男性松果体区肿瘤患儿的性早熟是假性性早熟,肿瘤分泌HCG导致血清HCG异常增高是性早熟的主要原因。     

Melatonin and mammary pathological growth

In this article we review the state of the art on the role of the pineal gland and melatonin in mammary cancer tumorigenesis in vivo as well as in vitro. The former hypothesis of a possible role of the pineal gland in mammary cancer development was based on the evidence that the pineal, via its main secretory product, melatonin, downregulates some of the pituitary and gonadal hormones which control mammary gland development and are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, thereby influencing their proliferative rate. Other possible origins of melatonin's antitumoral actions could be found in its antioxidant or immunoenhancing properties. The working hypotheses of most experiments were that the activation of the pineal gland, or the administration of melatonin, should give rise to antitumoral behavior; conversely, suppression of the pineal gland or melatonin deficits should stimulate mammary tumorigenesis. From in vivo studies on animal models of tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland, or the administration of melatonin, enlarge the latency and reduce the incidence and growth rate of chemically induced mammary tumors, while pinealectomy usually has the opposite effects. The direct actions of melatonin on mammary tumors have been suggested because of its ability to inhibit, at physiological doses (1 nM), the in vitro proliferation and invasiveness of MCF-7 human breast cancer cells. The fact that most studies have been performed on two models, chemically induced mammary adenocarcinoma in rats (in vivo studies) and the cell tumor line MCF-7 (in vitro studies), makes the generalization of the results somewhat difficult. However, the characteristics of these actions, comprising different aspects of tumor biology such as initiation, proliferation, and metastasis, as well as the doses (physiological range) at which the effect is accomplished, give special value to these findings. On the strength of these data, the small number of clinical studies focusing on the possible therapeutic value of melatonin on breast cancer is surprising.     

Anterior optic gliomas with precocious or pseudoprecocious puberty

5 patients with gliomas of the anterior optic pathways, histologically assessed or with strong diagnostic evidence, who developed precocious or pseudoprecocious puberty (2 cases) before the operation or after radiation treatment, are presented. Only 2 patients presented familial and/or personal evidence of neurofibromatosis. The production mechanism of these sexual changes is discussed.     

Experience with pineal region tumors

The results are reported of a retrospective review of the presentation and outcome of 43 pineal region tumors treated from 1982 to 1996, including 20 identified tumors: 5 germinomas, 8 teratomas, 2 embryonal carcinomas, 1 endodermal sinus tumor, 2 pineocytomas and 2 pineoblastomas. Of the 43 tumors reviewed, 36 were located in the pineal region, 5 in the suprasellar, and 2 in both the pineal and suprasellar regions. Twenty patients underwent surgical resection: total in 6 and partial in 10, while only a biopsy was taken in 4 cases. Fifteen patients were managed on the basis of serum CSF tumor markers and radiation response. Twenty-three patients with germinomas received radiotherapy (RT) and had a 5-year survival rate of 87%. Fifteen patients with non-germinomatous germ cell tumors received RT and chemotherapy following direct surgery, and 5 died (mortality rate of 33.3%). The overall survival rate of the 43 patients with pineal tumors was 79.1% (34/43) and the death rate was 20.9% (9/43). It is now recognized that the wide variety of tumor types found in the pineal region necessitates different modes of treatment, and improved microsurgical and stereotactic surgical techniques have made mortality and morbidity rates acceptably low. Because the radiation response and CSF cytology are not enough to determine optimum treatment, a tissue diagnosis should be obtained in all patients.     

Latency of intracranial germ cell tumors and diagnosis delay

Background

Intracranial germ cell tumors (GCTs) frequently take an insidious clinical course before diagnosis. To date, clinical latency has been discussed in the context of germinoma in the suprasellar area and basal ganglia.

Objective

In this study, we classified the clinical latency of intracranial GCTs into three categories and described their characteristics in order to understand the full spectrum of the phenomenon.

Methods

In a cohort of 181 patients with intracranial GCTs, 17 patients had a delayed diagnosis of more than 3 months (90 days) from the initial brain magnetic resonance imaging to the definitive GCT diagnosis. Clinical records and radiological data of the patients were reviewed.

Results

The patients with a delayed diagnosis were categorized into three groups according to their tumor location: suprasellar (nine patients), basal ganglia (six patients), and pineal (two patients). Initial symptomatology corresponded with the tumor location: central diabetes insipidus for the suprasellar group, hemiparesis for the basal ganglia group, and precocious puberty for the pineal group. The overall survival of patients with germinoma and delayed diagnosis was significantly shorter than that of patients who were diagnosed within 3 months (P?=?0.002).

Conclusions

Clinical latency and delayed diagnosis are not restricted to germinomas in the suprasellar area and basal ganglia; they are canonical features of intracranial GCTs including pineal non-germinomatous GCTs. Early detection and proactive diagnosis of these tumors are required because diagnosis delay may negatively influence patient survival.     

Pinealoblastomas in children

Introduction Series of pinealoblastomas (PB) usually comprise small number of cases as this tumor type is extremely rare and occurs mainly in childhood (especially under 9 years of age). Frequently, PB are reported together with others pineal parenchymal tumors (PPT) or pineal tumors, making characterization far from adequate.Materials and methods Our series of CNS pediatric tumors comprises 1,350 cases of whom 16 are PPT, 12 PB, two pineocytomas (PC), and two mixed or transitional tumors (PC/PB). We have only analyzed the PB considering clinical features, treatment strategy, prognosis, recurrences, and mortality.Results PB represented 0.89%. Mean age was 7 years. Male–female ratio was 8/4. All patients complained of increased intracranial pressure, eight presented ocular symptoms, two cerebellar, and one endocrine disturbances. Patients underwent CT scans and/or MRI. All children had negative serum and CSF markers and only one case had positive tumor cells in the CSF on admission. Hydrocephalus (12/12) was treated with ventriculoperitoneal shunt in 11/12 and endoscopic third ventriculostomy (ETV) in 1/12. We performed 11 surgical procedures (seven by occipital transtentorial approach) and one endoscopic biopsy. Total removal was achieved in two, partial removal (50–90%) in seven, and biopsy in three patients or <50%. Adjuvant therapy included radiotherapy and chemotherapy. Recurrences appeared in 8/12 cases (mean time of recurrence=27.28 months). Six patients died (mean survival=29.55 months). Mean follow up for the six patients alive was 54 months and mean follow up for all 12 children was 38.7 months.Conclusion In our opinion, PB have a poor prognosis and are very aggressive, especially in small children. Survival rate at 1 and 5 years in the present series is 66.6% (8/12) and 50% (6/12), respectively. We propose an algorithm for the treatment of pediatric patients with PB.     

Pineal parenchymal tumor of intermediate differentiation with cytologic pleomorphism

We report a case of pineal parenchymal tumor in a 33‐year‐old man incidentally detected by radiological examination. The MRI showed an unhomogeneously enhanced, small tumor (approximately 1 cm in size) in the pineal region. A tumor specimen was obtained at endoscopic biopsy. Routine histology showed a highly cellular tumor characterized by a predominance of small cells showing high nuclear : cytoplasmic ratio and moderate nuclear atypia, pleomorphism including giant cells and an absence of pineocytomatous rosettes. Mitotic figures were rare (approximately 1 per 10 high‐power fields). Tumor necrosis was not evident. Immunohistochemically, the neoplastic cells showed positivity for neural markers (neurofilament protein, synaptophysin) and pinealocyte‐associated antibodies (PP1, PP5, PP6), but not for glial fibrillary acidic protein or S‐100. The MIB‐1 labeling index was relatively high (6.3%). Ultrastructurally, there was some evidence of pinealocytic differentiation, such as vesicle‐crowned rodlets (synaptic ribbons) and paired twisted filaments in neoplastic cells. Thus, the tumor was confirmed as a pineal parenchymal tumor of intermediate differentiation by histology, immunohistochemistry and electron microscopy. This case indicates that marked cytologic pleomorphism can occur in pineal parenchymal tumors of intermediate differentiation.     

Late-onset post-irradiation vasculopathy of the posterior cerebral vasculature

Radiotherapy is extensively used in the treatment of malignant tumors of the central nervous system, but may also cause considerable morbidity and mortality, probably through damage to the remarkably vulnerable vascular system. We present two cases of infarction in the posterior cerebral vasculature related to earlier irradiation for a pineal gland tumor. Two patients were irradiated for a pineal gland tumor in young adulthood. Respectively 20 and 35 years later, they presented with a progressive neurological decline, related to early progressive atherosclerosis in the posterior cerebral vasculature. In conclusion, irradiation of the posterior cerebral territory may produce precocious atherosclerosis of posterior circulation vasculature, even decades later. When a progressive clinical decline with accumulating ischemic events is observed, together with signs of atherosclerosis, radiotherapy-related vasculopathy may be considered.     

Pineal ganglioglioma with premature thelarche

We report a case of a 6-year-old girl with a ganglioglioma in the pineal region presenting with a rare clinical picture of premature thelarche. Intracranial gangliogliomas are rare, especially in the pineal region. Their character, origin, treatment, and prognosis remain controversial. The pathophysiology of precocious puberty associated with pineal ganglioglioma is discussed.     

Studies on the effects of the pineal hormone melatonin on an androgen-insensitive rat prostatic adenocarcinoma,the Dunning R 3327 HIF tumor

Summary The effects of the pineal indole melatonin on a transplantable androgen-insensitive fast-growing rat prostatic adenocarcinoma, the Dunning R 3327 HIF tumor, were examined. Afternoon injections of melatonin given to intact male rats enhanced tumor growth, while leading to a reduction in the weights of gonads and dorsal and ventral prostates. In anosmic hosts, this treatment had no effect on tumor growth or reproductive organ size. In castrated anosmic hosts, melatonin injections led to reductions in the growth of tumors, when compared with those in castrated hosts. Continuously available melatonin, in beeswax pellets, had no effect on growth of these tumors. These results are discussed in relation to the anticancer effects of melatonin and the effects of tumors on endogenous melatonin rhythms.     

Immunohistochemical characterization of pineal parenchymal tumors using novel monoclonal antibodies to the pineal body

To characterize the immunohistochemical nature of pineal parenchymal tumors (PPT), we examined nine cases of normal pineal bodies and 23 cases of PPT using several neuronal and glial antibodies and 10 novel monoclonal antibodies raised against human pineal tissue. The PPT were classified into four pineocytoma, five pineal parenchymal tumor of intermediate differentiation (Int‐PPT), and 14 pineoblastoma. The pinealocytes, parenchymal cells of the pineal body, were labeled with five neuronal and seven pineal monoclonal (from PP1 to PP7) antibodies in the normal pineal bodies. The subjects ranged from 3 to 85 years old, 12 female and eight male subjects were studied. Antibodies to glial cells PI1, PI2 and PX1, stained interstitial cells of the pineal body. Many of the PPT showed positive immunostaining for pinealocyte‐associated antigens and neuronal markers. The intensity of immunostaining showed some association with the degree of differentiation of the tumor, but there was a considerable variety of staining from case to case. The pineocytomas are more immunopositive than are the Int‐PPT or pineoblastoma for neuronal and pinealocyte‐associated antibodies. In particular the neurofilament protein (NFP)68 kDa, PP1 and PP6 showed significant differences of reactivity between pineocytoma, Int‐PPT and pineoblastoma, when compared in groups showing extensive positive staining (positive staining in almost all areas of the tumor). By using three representative antibodies, anti‐NFP68kDa, PP1 and PP6, we were able to make a clear distinction between pineoblastoma, Int‐PPT and pineocytoma. Glial fibrillary acidic protein (GFAP), PI1 and PI2 antibodies only occasionally showed a small number of positive cells in the tumor, and thus we considered these cells to be non‐neoplastic interstitial cells or reactive astrocytes entrapped in the tumor. Our data suggest that the glial differentiation of PPT may occur, but that it seems to be a very rare event.     

Gonadotropin, as a tumor marker, in body fluid and tumor tissues of germ cell tumors

The value of gonadotropin in the body fluids of germ cell tumor patients is its usefulness as a tumor marker. It is also used for differential diagnosis and/or judgement of therapeutic effects. In order to clarify the most effective value of gonadotropin as a tumor marker in the body fluids, we compared the value in serum, liquor and urine with one another. The liquor contained highest (1650 IU/l) value of gonadotropin in the primary intracranial germ cell tumors, mostly in choriocarcinoma. But the gonadotropin value was highest (3050 IU/l) in the serum of secondary intracranial choriocarcinoma. Chiasmal germ cell tumor, except choriocarcinoma, which does frequently secrete gonadotropin (alpha, beta) showed moderate or very high values in the liquor. However, pineal germ cell tumors rarely secrete gonadotropin and sometimes mild high value are obtained in the serum without gonadotropin secretion immunohistochemically. In such cases, the gonadotropin may be increased by indirect mechanism of gonadotropin-secretion following pineal disorder. In most of such cases, the gonadotropin was not human chorionic gonadotropin (HCG) but lutein hormone (LH). Because alpha-subunit of such gonadotropin has the same structure, their antibodies show immunologic cross reaction. So, a count of beta-subunit gonadotropin in the serum or liquor is the best way for differential diagnosis or judgement of therapeutic effects. From our results, it is considered that the tumor secretes HCG if the serum beta-HCG value was higher than 30 IU/l, and that it doesn't secrete HCG if beta-HCG value was lower than 10 IU/l or non calculable. The mild increased HCG may be caused by hypothalamo-diencephalic disorder such as pineal tumor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha rhythm and the pineal gland.

Alpha rhythm is classically described as a bilateral posterior rhythm of substantially constant frequency in the range of 8-13 Hz which is enhanced by mental relaxation and blocked by attention. Since the full expression of alpha rhythm has been shown to occur coincident with puberty, it is possible that the establishment of alpha rhythm is subject to neuroendocrine influences which govern psychosexual maturation. There is ample evidence to indicate that the pineal gland is implicated in cerebral maturation and psychosexual development. Nocturnal plasma melatonin levels have been shown to decline progressively throughout childhood reaching a nadir at puberty. Since administration of melatonin has been reported to block alpha rhythm, it is proposed that the progressive decline in melatonin secretion during childhood facilitates the maturation of the alpha rhythm. Consequently, the presence of alpha rhythm could be used as a neurophysiological marker for the activity of the pineal gland and disorders associated with absent or delayed maturation of the alpha rhythm such as autism, dyslexia, personality disorders, epilepsy, Tourette's syndrome, and schizophrenia might be related to disturbances of pineal melatonin functions in early life. Moreover, since the EEG patterns associated with cerebral immaturity (i.e., slowing, absence of alpha activity) are more pronounced in the left hemisphere, this hypothesis implies differential influence of the pineal gland on hemispheric maturation potentially accounting for the vulnerability of the left hemisphere to cerebral insults.