Re-evaluation of the significance of cerebrospinal fluid human chorionic gonadotropin in detecting intracranial ectopic germinomas

This study was conducted to establish a reference value for cerebrospinal fluid (CSF) human chorionic gonadotropin (hCG) levels. We also evaluated the sensitivity of CSF hCG as a biomarker to detect intracranial ectopic germinomas that arise in rare sites other than the pineal and suprasellar regions. CSF hCG was measured in 201 male patients who had various types of neurological disease (not tumours of germ cell origin or other malignant tumours). A reference value of 1.009 U/L was established, and the CSF hCG level among different age groups was not significantly different. CSF and serum hCG were measured before and after radiotherapy in 14 consecutive patients with intracranial ectopic germinomas. The CSF hCG levels were all above 1.009 U/L before radiotherapy. In male patients, a CSF hCG value above 1.009 U/L suggests abnormal intrathecal hCG secretion. These results demonstrate that the CSF hCG assay is a sensitive method for diagnosing intracranial ectopic germinoma.     

Intracranial germ cell tumors: pathobiological and immunohistochemical aspects of 70 cases

Seventy cases of histologically verified intracranial germ cell tumor were reviewed: 43 germinomas, 16 immature teratomas, seven mature teratomas, two embryonal carcinomas, one choriocarcinoma, and one yolk sac tumor. The male-to-female ratio was 2.6:1. The average age was 19 years in patients with germinoma, 11 years in patients with immature teratoma, and 17 years in patients with mature teratoma. Duration of symptoms averaged 19 months for germinoma, three months for immature teratoma, and 11 months for mature teratoma. Sixty-six lesions were located in the midline. Fifty-eight percent of the germinomas arose anterior to the pineal gland, whereas 29% of the immature and 14% of the mature teratomas were located anteriorly. The histologic appearance of the germinomas was indistinguishable from that of the usual testicular seminoma. The immature teratomas contained tissue from all three germ layers and exhibited morphologic features of fetal tissue. Of 14 immature teratomas, seven contained, in addition, foci of other malignant germ cell elements; thus, there were two teratocarcinomas, two lesions with germinoma and immature teratoma, two lesions with extensive rhabdomyoblastic differentiation in an immature teratoma, and one lesion with both germinoma and embryonal carcinoma in addition to immature teratoma. The seven mature teratomas consisted of fully differentiated epithelial and mesenchymal tissues. In 23 cases, immunoperoxidase stains for human chorionic gonadotropin (HCG), alpha-fetoprotein (AFP), and carcino-embryonic antigen (CEA) revealed patterns which, with minor exceptions, were essentially identical to those found in genital germ cell lesions. Survival was longest for patients with germinomas. In classifying germ cell tumors of the central nervous system, the World Health Organization's (WHO) classification of testicular germ cell tumors is preferable to its present classification of intracranial germ cell tumors.     

Therapeutic strategies and surgical results for pineal region tumours.

Until recently, surgery for pineal region tumours has met with poor results. Although experience remains limited, developments in imaging, surgical approaches, and microsurgery have improved outcomes. Over 26 years we treated 36 patients including: 24 with germinoma; four, teratoma; three, pineal cyst; and one each, embryonal carcinoma, choriocarcinoma, pineocytoma, pineoblastoma and metastasis. All 24 germinomas responded to radiotherapy, as did one case each for teratoma, pineoblastoma, and choriocarcinoma. Eight patients underwent resection, and one patient with germinoma had biopsy via endoscopy. Occipital transtentorial and parieto-occipital transcallosal approaches were used in three each, and infratentorial supracerebellar and a combined infratentorial supracerebellar and occipital transtentorial approach in one each. Total removal was achieved in four patients (50%), and subtotal removal in two. Postoperative complications resolved within 2 weeks. Two patients had recurrence and one had dissemination. All tumours except germinomas should be explored and diagnosed histologically. Current operative techniques allow safe, effective removal of pineal region tumours.     

Treatment strategy for intracranial primary pure germinoma

Object

This prospective randomized clinical study will address the efficacy of radiation (RT)-alone and combined with pre-RT chemotherapy (CTX) treatments and propose the novel standard treatment strategy for intracranial primary pure germinoma.

Materials and methods

Between 2005 and 2008, there were 54 patients diagnosed with intracranial primary pure germinomas in a single institute. Twenty-eight patients were enrolled. The mean age of the patients was 16.2 years (range 6–31 years). There were 19 men and 9 women (men/women ratio?=?2.1:1). There were 21 patients with solitary tumors and 7 with multiple tumors. These patients were randomized as RT-only treatment group (11 solitary and 3 multiple tumors) and combined (10 solitary and 4 multiple tumors, neo-adjuvant CTX followed by response-adapted RT) treatment group. The follow-up period for RT only group has a median of 58 months (mean 58.2 months, range 41–82 months), and for combine therapy group, the median was 68.5 months (mean 67.8 months, range 41–88 months). All 14 patients in the RT-only group showed complete response (CR) and no recurrence. Eleven patients in the combined group had CR and three patients had partial response after neo-adjuvant CTX. All patients responded to RT as CR without recurrence. At the time of analysis, all 28 patients were alive without evidence of disease.

Conclusion

Neo-adjuvant CTX for localized germinomas seems to be unnecessary as a method to reduce radiation dose in our RT protocol. However, the effective control of multifocal or disseminated germinoma can be achieved by neo-adjuvant CTX followed by response-adapted reduced dose RT.     

Intracranial germinomas in a father and his son

Background

Primary intracranial germ cell tumors (IGCTs) represent an uncommon category of neoplasms, and familial occurrence is rare. We present the first report of parent-child patients with pathologically confirmed pure germinomas.

Case report

A 36-year-old Japanese man presented with diabetes insipidus and hypopituitarism. Magnetic resonance imaging (MRI) revealed a mass lesion in the pituitary stalk, which was diagnosed as a pure germinoma by open craniotomy tumor biopsy. Seven years later, his 13-year-old son also presented with diabetes insipidus. MRI revealed mass lesions in the pituitary stalk and the pineal region. He underwent endoscopic tumor biopsy for the pineal lesion, which was diagnosed as a pure germinoma. Both the father and his son were treated with combined radiochemotherapeutic regimens and achieved complete remission after one to two cycles of chemotherapy.

Conclusion

Although there have been three previous case reports of familial germinoma, all of these involved sibling pairs. The present report represents the first parent-child cases. This type of familial occurrence suggests the possibility that germline mutations may also be involved in the development of IGCTs.     

脑脊液细胞学在脑生殖细胞瘤诊断中的应用及八例报告

目的 通过总结8例脑生殖细胞瘤患者的脑脊液细胞学结果,探讨脑脊液细胞学在脑生殖细胞瘤诊断中的价值.方法 总结2006年1月至2009年6月我院脑脊液细胞学发现肿瘤细胞的8例脑生殖细胞瘤患者,分析其临床特点、影像学和脑脊液细胞学结果.结果 8例患者中男性7例,女性1例.年龄13～25岁,分别以多饮、多尿和少汗等内分泌症状或神经科症状起病.神经科症状包括:头晕、头痛、智能减退、精神行为异常、复视、双下肢无力、尿便障碍等.神经影像学可见鞍上区和(或)松果体区占位、脑室扩张、室管膜和软脑膜强化、神经根增粗强化等.脑脊液绒毛膜促性腺激素3.2～1087.0 mIU/ml.脑脊液细胞学8例均见肿瘤细胞,呈中等大小的圆形,核大,核仁明显,胞质丰富,胞质内可见较多空泡.背景间有小淋巴细胞为主的炎性反应.过碘酸Schiff染色肿瘤细胞胞质中见阳性颗粒.4例行免疫细胞化学染色,其中2例抗胎盘碱性磷酸酶阳性;2例行Ki-67染色,阳性细胞分别占12%和20%.细胞角蛋白和癌胚抗原染色等阴性.结论 脑生殖细胞瘤患者的脑脊液细胞学结果特征明显,结合细胞免疫化学可以明确其类型及脑脊液播散,在诊断脑生殖细胞瘤过程中起着重要作用.

Abstract：

Objective To investigate the value of the cerebrospinal fluid ( CSF ) cytology in diagnosis of intracranial germinomas by reviewing the outcomes of CSF cytology of 8 patients with intracranial germinomas. Methods Eight patients with positive CSF cytology at our clinic from January 2006 to June 2009 were reviewed. Conventional cytology and immunocytochemistry of CSF were performed. The relevant literature on the subject was reviewed. Results The patients, including 7 male and 1 female, developed endocrinological or neurological symptoms at the age of 13 to 25, and the typical neurological presentation included vertigo, headache, mental and behavior disorders, double vision and weakness of legs. The CSF cell count ranged from 0 to 300 leukocytes per cubic and elevated in 7 cases, typically lymphocytic inflammation. CSF level of human chorionic gonadotropin was 3.2-1087.0 mIU/ml, higher than the individual serum level. On CSF cytology studies, typical tumor cells of germinima were found, which had positive particles in cytoplasm on periodic acid Schiff stain. All presents had lymphocyte inflammation ( small lymphocyte predominant ). On immunocytochemical studies of CSF, the tumor cells were positive on placental alkaline phosphatase and Ki-67 stains. Conclusions CSF cytology is clinically useful for diagnosis of primary intracranial germinoma. Further clinical and cytological studies will be necessary for a better understanding of the biology of these tumors.     

Germinoma involving the basal ganglia in children

Background Germinoma originating in the basal ganglia is rare, and the majority of reported papers have been from Japan. In a collection of the first 500 cases of primary brain tumors in children in Taipei Veterans General Hospital, six pure germinomas with tissue diagnosis situated in this location. Materials and methods We reviewed the clinical features, neuroimaging studies, tumor markers, management, and outcome of these six patients. Results All of them were boys. The median age of onset of symptoms was 9.7 years. They uniformly presented with hemiparesis. The average duration of symptoms before surgical management was 1 year. One patient had bilateral basal ganglia tumors. Serum β-human chorionic gonadotropin levels was elevated (128 mIU/ml) in one patient. Longitudinal neuroimaging studies in four patients clearly showed that the tumor arose as a tiny lesion at the lenticular nucleus. Five patients had cysts within tumors. Five patients received partial, subtotal, to total resection. One patient had stereotactic biopsy of the tumors. Postoperative primary adjuvant therapies included radiotherapy, chemotherapy alone, and combined chemotherapy and radiotherapy. Five patients survived, and one patient died of radiation-induced sarcoma with median follow-up period of 13.7 years. Local recurrence was observed in all of three patients after solitary postoperative chemotherapy. Conclusions The lenticular nucleus is a significant locus for germinomas and can be bilateral. Although rarely reported in Western countries, it does exist in Taiwan as well. Treatment of germinomas in this specific location is similar to germinoma in other intracranial locations.     

Primary pontomedullary germinoma in a 12 year old boy

Primary intracranial germinomas are rare tumors, accounting for approximately 1–4% of all intracranial tumors. Intracranial germinomas are more commonly found in the suprasellar and pineal midline structures of the brain. Brainstem and posterior fossa germinomas are rarer still, with few reported cases in the literature, and little discussion of their presentation, management and clinical outcome. A unique case of pontomedullary germinoma, diagnosed in a 12-year-old boy, is described. Only six previous cases of lower brainstem germinoma have been reported, with varying modes of presentation and a lack of definitive management guidelines. Of these, all occurred in either females or a patient with Klinefelter’s syndrome. We report the first case of a lower brainstem germinoma in a male without known genetic abnormality. Tumor remission was achieved with partial surgical resection, chemotherapy and radiotherapy.     

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.     

Metastatic spinal intramedullary germinoma with elevated cerebrospinal fluid chorionic gonadotropin: a case report

We treated a patient whose unusual recurrent germinoma illustrates the diagnostic value of measuring human chorionic gonadotropin beta subunit (HCG-beta) in cerebrospinal fluid (CSF) and serum. A 25-year-old man with a suprasellar germinoma and ventricular dissemination was treated successfully with systemic chemotherapy and cranial irradiation. Six years later he developed progressive numbness and weakness in both upper extremities. Magnetic resonance imaging (MRI) disclosed an intramedullary spinal cord tumor in the cervical region. The CSF concentration of HCG-beta was elevated and exceeded that in serum. After completion of systemic chemotherapy and spinal irradiation, symptoms subsided and the tumor was no longer evident on MRI. Based on the patient's history and the rapid response of the tumor to treatment, the spinal cord tumor was considered a metastatic intramedullary spinal germinoma representing CSF dissemination via the central canal.     

Rapidly growing giant suprasellar tumor in a high-risk child: treatment strategy and role of neuroendoscopic surgery in slit-like ventricles

RATIONALE: Suprasellar tumors are common in the pediatric population and exhibit a wide range of pathological appearance and behavior. Although rare, pure suprasellar germinomas carry worse prognosis than other locations. METHODS: We present a case of a 10-year-old girl treated with therapeutic anticoagulation for previous cardiac valvular replacement, who presented with rapidly growing giant (>4 cm) suprasellar germinoma. Neoadjuvant chemotheraphy was effective and the dilated ventricles became slit-like. The fine free-hand maneuver using a fine rigid-rod neuroendoscope. "Oi-Samii Handy Pro" made it possible to obtain the tissue diagnosis. RESULTS: Complete remission was achieved using neoadjuvant chemotherapy, minimally invasive neuroendoscopic surgery, then followed by specific chemoradiotherapy. CONCLUSION: The role of neuroendoscopic procedure, performed in a difficult situation with normalized size of the ventricles, was emphasized.     

颅内生殖细胞瘤的临床治疗探讨

目的：探讨颅内生殖细胞瘤的综合治疗方法。方法临床诊断颅内生殖细胞瘤１３例，其中孤立型８例，侵袭型４例，播散型１例；治疗上对孤立型采取局灶放疗同时联合顺铂、足叶乙甙化疗，侵袭型与播散型加用氨甲喋呤脑或鞘注给药化疗。结果肿瘤完全消失１１例，瘤体缩小９０％以上２例，随访０．３－４．５年（平均２．７年），无１例复发，全部病例生存状况良好。结论治疗上针对肿瘤的临床分型，采取局灶放疗与不同的化疗方案联合能有效     

Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis

OBJECTIVE: To determine the value of vascular endothelial growth factor (VEGF) in CSF as a marker for carcinomatous meningitis (CM). METHODS: The concentration of VEGF was measured by ELISA in matched samples of CSF and serum collected from 162 patients. These included patients with solid tumors with CM (n = 11) or brain metastases without concomitant CM (n = 12), paraneoplastic neurologic syndromes (n = 4), viral (n = 15) and bacterial (n = 20) meningitis, and a variety of non-neoplastic and noninfectious neurologic diseases (n = 100). Using CSF/serum albumin ratios, the VEGF index was calculated to estimate the proportion of intrathecally produced VEGF. Immunohistochemical staining for VEGF was performed in a brain metastasis from a mammary carcinoma associated with CM. RESULTS: High VEGF levels (median 6,794.8 pg/mL) were found in CSF of all patients with CM, whereas VEGF levels in matched sera were comparable to other disease groups. In patients with CM, the concentration of VEGF in CSF decreased significantly following antineoplastic treatment. In CSF samples from patients with brain metastases without concomitant CM, VEGF was not detectable. Median VEGF concentration in CSF from patients with acute bacterial meningitis was 38.6 pg/mL, with only 9 of these 17 patients showing detectable VEGF levels in CSF. The VEGF indices in patients with bacterial meningitis were significantly lower than in tumor patients with CM (<22.8 versus >62.3), suggesting that the proportion of intrathecally produced VEGF is much higher in patients with CM as compared with patients with bacterial meningitis. Patients without neoplastic or infectious neurologic disorders consistently showed VEGF levels in CSF below the assay detection limit of 25 pg/mL. Immunohistochemistry revealed strong cytoplasmic staining for VEGF in a metastatic lesion from breast cancer infiltrating the meninges. CONCLUSION: In patients with carcinomatous meningitis, significant amounts of VEGF are released into CSF. This study yields preliminary evidence that VEGF in CSF may be a useful biologic marker for both the diagnosis and evaluation of treatment response in carcinomatous meningitis.     

Serum IgG,IgA and IgM concentration in 1,038 patients with various neurological disorders

Summary Concentration of serum IgG, IgA and IgM in 1,038 unselected patients with various neurological diseases was determined. In 521 instances, the levels of CSF IgG, IgA and IgM were also established. In serum, the most frequent selective quantitative abnormality was found in the IgA concentration. In CSF, an increased level of IgG with normal IgA concentration and undetectable IgM was established about 8 times more frequently than isolated increase of CSF IgA. Selective quantitative abnormalities in serum IgG were observed in 35% of patients with subacute sclerosing panencephalitis as compared to 5% in instances in the definite MS group. Abnormal bands in the serum gamma-globulin field were most frequently seen in electropherograms from patients with subacute sclerosing panencephalitis, in cases of malignant lymphoproliferative disorders and in patients with definite MS. No correlation between the concentration of serum and CSF immunoglobulins could be established. Most frequent quantitative abnormalities in serum IgG, IgA and/or IgM were established in malignant lymphoproliferative disorders, in patients with myopathies including myositides and in subacute or chronic inflammatory CNS disorders. Highest incidence of increased CSF IgG, IgA and/or IgM concentration was detected in patients with inflammatory CNS disease, in instances of definite MS and in malignant lymphoproliferative disorders with CNS symptomatology. Increased CSF IgG and IgA concentration with detectable levels of IgM in patients with elevated CSF total proteins indicated alterations in the blood/CNS barrier structures.Supported by PHS grants NB05450 and 06793.     

Neuroendocrine aspects of pineal tumors

The evaluation and treatment of pineal region tumors has changed dramatically in the past decade. New imaging techniques result in earlier diagnosis. Surgical techniques now permit removal of benign tumors (about one third of cases). Pathologic diagnosis is obtained for the remainder, and postoperative therapy can be planned rationally. Germ cell tumors pose a particularly difficult problem for the pathologist because they often contain mixed germ cell elements. Biologic markers, beta HCG and AFP, aid diagnosis and can be monitored in serum and CSF to assess response to treatment. Only boys develop precocious puberty with pineal tumors. What appears to be puberty is actually pseudoprecocious puberty, due to ectopic production of HCG by their neoplasms (choriocarcinomas or germinomas with syncytiotrophoblastic giant cells). HCG can stimulate tests to produce testosterone, but FSH is necessary (together with LH or HCG) to stimulate ovaries to produce estrogen. Diabetes insipidus with pineal tumors is usually due to spread to the hypothalamus by ventricular seeding, but we report a case of aqueductal stenosis with diabetes insipidus resulting from a massively dilated third ventricle. Rarely, hydrocephalus may trigger true precocious puberty, a syndrome easily differentiated from pseudoprecocious puberty by endocrinologic tests. There are no biologic markers to diagnose pineal parenchymal tumors. Elevation of melatonin in plasma or CSF and increased tumor biosynthetic activity has been reported in isolated cases, but the range of melatonin values in normals is very wide, and melatonin levels do not correlate with specific pathologic tumor types. Both parenchymal and nonparenchymal tumors may increase melatonin nonspecifically by interfering with regulatory mechanisms of the normal pineal gland.     

C/EBP homologous protein investigation in the serum and cerebro-spinal fluid of relapsing-remitting multiple sclerosis patients

The exact determination of endoplasmic reticulum (ER) stress-associated proteins is not completely elucidated in the multiple sclerosis (MS) patients. We measured CHOP concentrations in the serum and cerebro-spinal fluid (CSF) of relapsing-remitting MS (RRMS) patients (n = 20) in comparison with the non-MS control group (n = 20) to determine whether this marker could be detected in the body fluids of RRMS patients. CHOP marker was not detectable in all harvested CSF samples. However, its levels were detectable in all serums harvested from both non-MS and RRMS patients and its levels in the latter group were not significantly higher than those of the non-MS control group (P value = 0.265). CHOP was not detectable in the CSF of RRMS patients in spite of the recent reports on the RRMS autopsies. Additionally, there were not any significant correlations (Spearman's correlation) between both of EDSS score and age with CHOP serum concentrations in all subjects.     

Understanding the Treatment Strategies of Intracranial Germ Cell Tumors: Focusing on Radiotherapy

Intracranial germ cell tumors (ICGCT) occur in 2-11% of children with brain tumors between 0-19 years of age. For treatment of germinoma, relatively low radiation doses with or without chemotherapy show excellent 10 year survival rate of 80-100%. Past studies showed that neoadjuvant chemotherapy combined with focal radiotherapy resulted in unacceptably high rates of periventricular tumor recurrence. The use of generous radiation volume which covers the whole ventricular space with later boost treatment to primary site is considered as standard treatment of intracranial germinomas. For non-germinomatous germ cell tumors (NGGCT), 10-year overall survival rate is still much inferior than that of intracranial germinoma despite intensive chemotherapy and high-dose radiotherapy. Craniospinal radiotherapy combined with cisplatin-based chemotherapy provides the best treatment outcome for NGGCT; 60-70% of overall survival rate. There is a debate on the surgical role whether surgery can contribute to improved treatment outcome of NGGCT when added to combined chemoradiotherapy. Because higher dose of radiotherapy is required for treatment of NGGCT than for germinoma, it is tested whether whole ventricular irradiation can replace craniospinal irradiation in intermediate risk group of NGGCT to minimize radiation-related late toxicity in the recent studies. To minimize the treatment-related neural deficit and late sequelae while maintaining long-term survival rate of ICGCT patients, optimized administration of chemotherapy and radiotherapy should be selected. Use of technically upgraded radiotherapy modalities such as intensity-modulated radiotherapy or proton beam therapy is expected to bring an improved neurocognitive outcome with longitudinal assessment of the patients.     

Treatment failure in intracranial primary germinomas

Object A radiation dose of 40–50 Gy is able to produce a cure rate of more than 90% in intracranial pure germinoma. However, many attempts have been made to reduce the dose and volume of radiation without compromising the disease control rate because of the toxicity of irradiation. This retrospective study is intended to provide the physician with an appropriate therapeutic strategy. Materials and methods We reviewed a series of 10 recurrent germinomas among 117 germinomas diagnosed histologically or clinically between 1979 and 2002. These patients involved underwent three different treatment modalities; radiation alone (N = 71), chemotherapy alone (N = 9), and combined therapy (N = 37). The 10-year overall and relapse-free survival rates were 97 and 93% in the radiation alone group, 89 and 67% in the chemotherapy alone group, and 92 and 92% in the combined therapy group, respectively. As expected, both radiation therapy and combined therapy were effective in controlling the disease. Tumor recurrence was closely related to the volume of radiation but not to the dose of radiation. If the tumor bed and craniospinal axis were fully covered, the radiation dose might be reduced. Chemotherapy alone showed earlier recurrence and a higher tumor recurrence rate. In the case of combined therapy, chemotherapy was useful in reducing the radiation dose but revealed some toxicity (death of two patients). Conclusions The investigation of a possible further dose reduction seems worthwhile. Radiation therapy alone with a dose of less than 40 Gy should be compared with ongoing chemotherapeutic protocols combined with low-dose irradiation.     

Individual cerebrospinal fluid (CSF) proteins in the evaluation of increased CSF total protein

Summary The concentrations of 16 different proteins have been determined in unconcentrated CSF and in serum by radial immunodiffusion. The study included 20 patients with different neurological disorders and with total protein concentrations in CSF ranging between 26 and 299 mg per 100 ml. A simultaneous increase of most of the CSF proteins quantitated was found with increased total protein concentrations. A positive, statistically significant correlation between the concentrations of haptoglobin, ₂-macroglobulin and -lipoprotein in CSF, and the total protein concentration in CSF, however, was first obtained when the concentration of the protein in serum was also taken into account.The concentration of individual proteins in CSF seems to be influenced by the molecular weight of the proteins, and patients with normal, as well as increased, total protein concentrations in CSF seem to have a mechanism favouring the entrance into the CSF of proteins with low molecular weights.The following exceptions from these general rules became obvious: 1. The concentrations of prealbumin and transferrin in most CSF specimens, and the concentration of immunoglobulin G in some of the multiple sclerosis CSF specimens were higher than would be expected on the basis of the molecular weights and the concentrations in serum; 2. the concentration of gamma-trace protein in CSF was also considerably higher than would be expected on the basis of the molecular weight and the concentration in serum; in addition, no correlation existed between the concentration of this protein in CSF and the total protein concentration in CSF; 3. a positive correlation was shown to exist between the concentration of beta-trace protein in CSF and the total protein concentration in CSF, whereas the concentration in serum was unmeasurable, indicating a source other than serum for the increasing concentrations of this protein in CSF.Read in part before the Second International Meeting of the International Society for Neurochemistry, Milan, 3rd September, 1969 (Link, H., and O. Zettervall: Increased cerebrospinal fluid (CSF) total protein, a sign of blood-CSF-barrier damage. Report, Second International Meeting of the International Society for Neurochemistry, edited by Paoletti, R., pp. 269–270. Milan: Tamburini Editore 1969).     

Bifocal germinomas in the pineal region and hypothalamo-neurohypophyseal axis: Primary or metastasis?

Whether bifocal germinomas (BFGs) synchronously presenting within the pineal region and the hypothalamo-neurohypophyseal axis (HNA) are primary germinomas of dual-origin remains to be elucidated. We analyzed MRI images and clinical features of 95 neurohypophyseal germinomas and 21 BFG patients and developed a tentative definition of the BFGs. We found dual-primary BFGs (true BFGs) do exist. The fundamental difference between primary and metastatic HNA germinomas was the direction of tumor growth. For a true BFG, the primary HNA tumor grew from the neurohypophysis toward the hypothalamus and almost invaded the whole pituitary stalk. For a false BFG (primary pineal germinoma with HNA metastasis), the metastatic HNA tumor first appeared at the third ventricular floor (TVF), grew toward the neurohypophysis, but commonly did not invade the inferior pituitary stalk. Compared to false BFGs, true BFGs commonly had diabetes insipidus as the first symptom, dysfunction of the anterior pituitary, no high-intensity MRI signal at the posterior pituitary, a larger extension of the HNA tumor, and fewer numbers of remote lesions from cerebrospinal fluid seeding. Accordingly, 12.8% (12/96) of our germinoma patients had true BFGs, and of these, 58.3% (7/12) were free of remote metastases and warranted treatment with limited radiotherapy. True BFGs with remote metastases and all false BFGs should be treated with craniospinal irradiation. We provided evidence for the diagnosis of true BFGs that is useful for radiotherapy strategy, suggesting that the existence of metastasis to other locations is not a diagnostic criterion for a true BFG.