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Molecular Pathology and Targeted Therapies for Personalized Management of Central Nervous System Germinoma. J Pers Med 2021; 11:jpm11070661. [PMID: 34357128 PMCID: PMC8306901 DOI: 10.3390/jpm11070661] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/05/2021] [Accepted: 07/10/2021] [Indexed: 12/19/2022] Open
Abstract
Intracranial germinomas are rare tumours, usually affecting male paediatric patients. They frequently develop in the pineal and suprasellar regions, causing endocrinological disturbances, visual deficits, and increased intracranial pressure. The diagnosis is established on magnetic resonance imaging (MRI), serum and cerebrospinal fluid (CSF) markers, and tumour stereotactic biopsy. Imaging techniques, such as susceptibility-weighted imaging (SWI), T2* (T2-star) gradient echo (GRE) or arterial spin labelling based perfusion-weighted MRI (ASL-PWI) facilitate the diagnosis. Germinomas are highly radiosensitive tumours, with survival rates >90% in the context of chemoradiotherapy. However, patients with resistant disease have limited therapeutic options and poor survival. The aim of this review is to highlight the genetic, epigenetic, and immunologic features, which could provide the basis for targeted therapy. Intracranial germinomas present genetic and epigenetic alterations (chromosomal aberrations, KIT, MAPK and PI3K pathways mutations, DNA hypomethylation, miRNA dysregulation) that may represent targets for therapy. Tyrosine kinase and mTOR inhibitors warrant further investigation in these cases. Immune markers, PD-1 (programmed cell death protein 1) and PD-L1 (programmed death-ligand 1), are expressed in germinomas, representing potential targets for immune checkpoint inhibitors. Resistant cases should benefit from a personalized management: genetic and immunological testing and enrolment in trials evaluating targeted therapies in intracranial germinomas.
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Huang ZC, Dong Q, Song EP, Chen ZJ, Zhang JH, Hou B, Lu ZQ, Qin F. Germinomas of the basal ganglia and thalamus: Four case reports. World J Clin Cases 2020; 8:4558-4564. [PMID: 33083418 PMCID: PMC7559660 DOI: 10.12998/wjcc.v8.i19.4558] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/29/2020] [Accepted: 08/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The early diagnosis of basal ganglia and thalamus germinomas is often difficult due to the absence of elevated tumor markers, and atypical clinical symptoms and neuroimaging features.
CASE SUMMARY Four male children aged 8 to 15 years were diagnosed with germinomas in the basal ganglia and thalamus by stereotactic biopsy from 2017 to 2019. All patients developed hemiplegia except patient 4 who also had cognitive decline, speech disturbance, nocturnal enuresis, polydipsia, polyuria, precocious puberty and abnormalities of thermoregulation. All four cases were alpha-fetoprotein and beta-human chorionic gonadotrophin (β-HCG) negative except patient 3 who had slightly elevated β-HCG in cerebrospinal fluid (CSF). No malignant cells were detected in the patients’ CSF. Brain magnetic resonance imaging findings were diverse in these patients with the exception of the unique and common characteristics of ipsilateral hemisphere atrophy, especially in the cerebral peduncle. All patients were diagnosed with germinomas of the basal ganglia and thalamus by stereotactic brain biopsy.
CONCLUSION Stereotactic brain biopsy is necessary to confirm the diagnosis of ectopic germinomas. Serial neuroimaging studies can not only differentiate disease but also determine the biopsy site.
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Affiliation(s)
- Zhen-Chao Huang
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Qing Dong
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - En-Peng Song
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zhi-Jie Chen
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Jin-Hua Zhang
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Bo Hou
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zheng-Qi Lu
- Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Feng Qin
- Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
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Outcomes of Local Radiation and Intensified Combined Intrathecal Methotrexate and High-dose Chemotherapy for Intracranial Germ Cell Tumors. J Pediatr Hematol Oncol 2020; 42:e551-e557. [PMID: 32398600 DOI: 10.1097/mph.0000000000001820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Many attempts to reduce radiation fields for intracranial germ cell tumors (iGCTs) remain unsuccessful. To assess the possibility of reduction, we analyzed registry data of 57 patients who mostly underwent local irradiation for iGCTs between 1997 and 2006. The recommended treatment for pure germinomas (PGNs) included 3 courses of cisplatin and etoposide followed by 24 Gy local irradiation. Intensified chemotherapy using a combination of cyclophosphamide and intrathecal methotrexate was recommended for human chorionic gonadotropin-producing germinomas (hCG-GNs) and nongerminomatous germ cell tumors (NGGCTs); both received 50.4 Gy local irradiation. High-dose chemotherapy was only administered for residual NGGCTs after chemoradiotherapy. Craniospinal irradiation was recommended only in metastatic cases. During the median follow-up of 114.8 months, 8 of 9 relapses from 24 PGNs occurred outside irradiation fields, with a 5-year progression-free survival (5-year PFS) of 75%±8.8%. Conversely, no recurrences occurred from 11 hCG-GNs, with a 5-year PFS of 100%. Eleven of 22 patients with NGGCTs received high-dose chemotherapy; the 5-year PFS was 81.3%±8.4%; 2 of 3 relapses occurred in the spinal cord. Thus, local irradiation for PGNs was insufficient without treatment intensification. The introduction of intensified chemotherapy improved outcomes of both patients with hCG-GNs and NGGCTs. However, the contributions of either modality remained unclear.
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Lee JW, Lim DH, Sung KW, Cho HW, Ju HY, Yoo KH, Koo HH, Kim JH, Suh YL, Shin HJ. Induction Chemotherapy Reduces Radiation Therapy Dose and Volume in the Treatment of Intracranial Germinoma: Results of the SMC-G13 Trial. Int J Radiat Oncol Biol Phys 2020; 108:649-656. [PMID: 32502506 DOI: 10.1016/j.ijrobp.2020.05.051] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 05/20/2020] [Accepted: 05/23/2020] [Indexed: 01/14/2023]
Abstract
PURPOSE We performed a prospective single-arm trial (NCT02782754) to explore the feasibility of reducing radiation therapy (RT) dose when induction chemotherapy is combined in the treatment of intracranial germinoma with beta-human chorionic gonadotropin levels <200 mIU/mL. METHODS AND MATERIALS All patients aged 3 to 35 years from November 2012 to June 2018 were eligible for this study. Four cycles of induction chemotherapy were given before RT. Carboplatin/etoposide and cyclophosphamide/etoposide regimens were used in alternation every 3 weeks. A dose of 18 Gy of craniospinal RT for metastatic tumors, whole brain RT for basal ganglia tumors, or otherwise whole ventricular RT followed by 12.6 Gy of boost RT to the primary tumor bed was administered after induction chemotherapy. The primary endpoint of this study was progression-free survival. RESULTS A total of 41 consecutive patients were enrolled (location: suprasellar in 12, pineal in 12, both suprasellar and pineal in 11, and basal ganglia in 6 patients). Eleven patients had leptomeningeal seeding. Toxicity during chemotherapy was mild, except for bone marrow suppression. Tumor status after induction chemotherapy was complete response in 33 patients and partial response in 8. All but 2 patients completed the scheduled treatment. All patients but 1 remained event free during a median follow-up of 3.4 (range, 0.3-7.0) years from diagnosis. The 1 patient experienced relapse and died of tumor bleeding. Late effects were not significant except for neuroendocrine dysfunction already present at diagnosis. Vertical growth and cognitive function were not significantly disturbed by treatment. CONCLUSIONS This study showed the feasibility of reducing RT dose/volume with induction chemotherapy in pathologically pure germinoma with elevated beta-human chorionic gonadotropin levels up to 200 mIU/mL.
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Affiliation(s)
- Ji Won Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Do Hoon Lim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ki Woong Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Hee Won Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hee Young Ju
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hong Hoe Koo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ji Hye Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yeon-Lim Suh
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hyung Jin Shin
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Aihara Y, Watanabe S, Amano K, Komatsu K, Chiba K, Imanaka K, Hori T, Ohba T, Dairoku H, Okada Y, Kubo O, Kawamata T. Placental alkaline phosphatase levels in cerebrospinal fluid can have a decisive role in the differential diagnosis of intracranial germ cell tumors. J Neurosurg 2019; 131:687-694. [PMID: 30265190 DOI: 10.3171/2018.3.jns172520] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 03/06/2018] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Placental alkaline phosphatase (PLAP) in CSF can provide a very high diagnostic value in cases of intracranial germ cell tumors (GCTs), especially in pure germinomas, to the level of not requiring histological confirmation. Unlike other tumor markers, reliable data analysis with respect to the diagnostic value of PLAP serum or CSF levels has not been available until now. This is the first systematic and comprehensive study examining the diagnostic value of CSF PLAP in patients with intracranial GCTs. METHODS From 2004 to 2014, 74 patients (average age 19.6 ± 10.6 years) with intracranial GCTs were evaluated using PLAP from their CSF and histological samples. Chemiluminescent enzyme immunoassay was utilized to measure CSF PLAP in the following tumor sites: pineal (n = 32), pituitary stalk, suprasellar (n = 16), basal ganglia (n = 15), intraventricular (n = 9), and cerebellar (n = 5) regions. In addition to classifying GCT cases, all patients underwent tumor biopsy for correlation with tumor marker data. RESULTS PLAP in combination with other tumor markers resulted in extremely high sensitivity and specificity of the diagnostic value of intracranial GCTs. Intracranial GCT cases were classified into 1) germinomas, both "pure" and syncytiotrophoblastic giant cell types (n = 38); 2) nongerminomatous GCTs, choriocarcinomas (n = 9) and teratomas (n = 4); and 3) nongerminomas, other kinds of tumors (n = 23). Consequently, all patients received chemoradiation therapy based on elevation of PLAP and the histopathological results. It was also speculated that the level of PLAP could show the amount of intracranial germ cell components of a GCT. PLAP was 100% upregulated in all intracranial germinoma cases. The absence of CSF PLAP proved that the tumor was not a germinoma. CONCLUSIONS The current study is the first systematic and comprehensive examination of the diagnostic value of the tumor marker PLAP in pediatric patients with intracranial GCT. Using the level of PLAP in CSF, we were able to detect the instances of intracranial germinoma with very high reliability, equivalent to a pathological diagnosis.
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Affiliation(s)
- Yasuo Aihara
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Sinichiro Watanabe
- 2Division of Internal Medicine and Clinical Laboratory Medicine, Minamisenju Hospital, Tokyo; and
| | - Kosaku Amano
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Kana Komatsu
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Kentaro Chiba
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Kosuke Imanaka
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Tomokatsu Hori
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Takashi Ohba
- 2Division of Internal Medicine and Clinical Laboratory Medicine, Minamisenju Hospital, Tokyo; and
| | - Hitoshi Dairoku
- 3Faculty of Human Sciences, University of Tsukuba, Ibaraki, Japan
| | - Yoshikazu Okada
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Osami Kubo
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
| | - Takakazu Kawamata
- 1Department of Neurosurgery, Tokyo Women's Medical University, Tokyo
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Basal Ganglionic Germinoma With Syncytiotrophoblastic Giant Cells Mimicking a Growing Hematoma. J Craniofac Surg 2019; 30:e306-e308. [PMID: 31166274 DOI: 10.1097/scs.0000000000005226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Basal ganglionic germinoma (BGG) with syncytiotrophoblastic giant cells (STGC) is a rare type of ectopic germ cell tumors with mild elevation of human chorionic gonadotropin level. Intratumoral hemorrhage is not uncommon for BGG, but presenting with repeated hemorrhage is very rare. Herein, we described an extremely rare case of BGG with STGC mimicking a growing hematoma. Furthermore, the characteristics, treatment, and prognosis of BGG with STGC were investigated and reviewed.
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Abstract
Background: The pineal gland, a small, pinecone-shaped organ deep within the brain, is responsible for producing melatonin. The gland consists of pineal parenchymal cells and glial cells that can form neoplasms. Pineal region neoplasms can also arise from germ cells and adjacent structures. This review focuses on detection of serum and cerebrospinal fluid (CSF) biomarkers of germ cell tumors and pineal parenchymal cell tumors, as these types comprise most neoplasms specific to the pineal region. Methods: For this review, we searched PubMed using the following keywords: biomarkers, germ cell tumor, germinoma, melatonin, pineal, pineal gland, pineal neoplasm, pinealoma, pineal parenchymal cell tumor, pineal region, and pineal tumor. We limited our search to full-text English articles and identified other relevant sources from the reference lists of identified articles. Results: Serum and CSF biomarker assays have a role in cases of suspected pineal germ cell or parenchymal neoplasms. Biomarkers including alpha-fetoprotein, beta-human chorionic gonadotropin, and placental alkaline phosphatase inform diagnosis and treatment and are important for monitoring germ cell tumor response to treatment. No biomarkers are currently available that inform diagnosis or treatment of pineal parenchymal tumors, although melatonin assays may have a role in monitoring response to treatment. Conclusion: Serum and CSF biomarkers in conjunction with clinical and radiographic evidence of a pineal region mass can inform the decision whether to undertake stereotactic biopsy or surgical excision or whether to proceed straight to medical treatment.
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Significance of human chorionic gonadotropin as a predictor of resistance to standard chemo-radiotherapy for pure germinoma. Neurosurg Rev 2017; 41:557-565. [DOI: 10.1007/s10143-017-0891-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 07/11/2017] [Accepted: 08/03/2017] [Indexed: 01/15/2023]
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Human chorionic gonadotropin is expressed virtually in all intracranial germ cell tumors. J Neurooncol 2015; 124:23-32. [PMID: 25994796 DOI: 10.1007/s11060-015-1809-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 04/20/2015] [Indexed: 12/19/2022]
Abstract
Human chorionic gonadotropin (hCG) production has been utilized as a diagnostic marker for germinoma with syncytiotrophoblastic giant cells (STGC) and choriocarcinoma. Elevated hCG in germinoma is considered to predict less favorable prognosis, and an intensive treatment strategy may accordingly be applied. However, there is some evidence that any germinoma may produce hCG to varying extent. We investigated mRNA expression of the hCG β subunit (hCGβ) using real time quantitative polymerase chain reaction in 94 germ cell tumors (GCTs). Most (93.3 %) GCTs showed higher expression levels compared with that of normal brain tissue (1.09 × 10(0)-1.40 × 10(5) fold). The expression was the highest in GCTs which harbor choriocarcinoma or STGC components. The expression level of hCGβ in germinoma was highly variable (1.09 × 10(0)-5.88 × 10(4) fold) in linear but not bimodal distribution. hCG concentrations in serum and CSF correlated with gene expression, especially when GCTs with single histological component were analyzed separately. The expression was not significantly associated with recurrence in pure germinoma. These results suggest that the serum/CSF hCG levels may need to be interpreted with caution as most GCTs appear to have the capacity of producing hCG irrespective of their histology. The clinical significance of ubiquitous hCG expression in GCTs needs further investigation.
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10
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Intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven CNS germinoma with elevated beta-human chorionic gonadotropin. J Neurooncol 2014; 117:279-85. [DOI: 10.1007/s11060-014-1381-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2013] [Accepted: 01/20/2014] [Indexed: 12/23/2022]
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Clinical use of (11)C-methionine and (18)F-FDG-PET for germinoma in central nervous system. Ann Nucl Med 2013; 28:94-102. [PMID: 24272066 PMCID: PMC3926980 DOI: 10.1007/s12149-013-0787-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 11/03/2013] [Indexed: 11/09/2022]
Abstract
Objective The purpose of this study was to examine the 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) findings of central nervous system (CNS) germinoma and the diagnostic utility of these findings. Methods We retrospectively evaluated the cases of 10 patients who were diagnosed with CNS germinoma according to their histopathological or clinical findings. All the patients underwent pretreatment MET and/or FDG-PET scans, and the resultant images were assessed qualitatively and quantitatively. In the qualitative assessments, we used 3- and 5-grade visual scoring systems for the MET- and FDG-PET images, respectively. In the quantitative assessments, the maximal standardized uptake value (SUVmax) and the ratio of the SUVmax of the tumor (T) divided by the mean SUV for the normal white or gray matter [T/N (WM), T/N (GM)], was calculated. Results The mean and SD values of SUVmax, T/N (WM), and T/N (GM) were 1.9 ± 1.4, 2.5 ± 1.3, and 1.7 ± 0.9 on MET-PET and 5.8 ± 2.2, 1.6 ± 0.5, and 0.8 ± 0.2 on FDG-PET, respectively. On MET-PET, only one lesion was not detected. On the other hand, on FDG-PET all of the lesions exhibited uptake values that were intermediate between those of the normal white matter and gray matter. Conclusion In terms of its tumor-contouring ability, MET is a good tracer for diagnosing CNS germinomas; therefore, MET-PET is considered to be useful for planning biopsies or surgery. Although FDG-PET is capable of detecting CNS germinomas, it produced insufficient image contrast in the present study. Further studies are needed before FDG-PET can be used in clinical examinations of CNS germinoma.
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Gonzalez-Sanchez V, Moreno-Perez O, Pellicer PS, Sanchez-Ortiga R, Guerra RA, Dot MM, Alfonso AMP. Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas. Ann Clin Biochem 2011; 48:433-7. [DOI: 10.1258/acb.2010.010074] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Lee D, Suh YL. Histologically confirmed intracranial germ cell tumors; an analysis of 62 patients in a single institute. Virchows Arch 2010; 457:347-57. [PMID: 20652714 DOI: 10.1007/s00428-010-0951-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2010] [Revised: 07/05/2010] [Accepted: 07/07/2010] [Indexed: 02/07/2023]
Abstract
This study was undertaken to document the clinicopathologic characteristics of histologically verified, primary intracranial germ cell tumors (GCTs), determine treatment outcomes, and to identify prognostic factors. The records of 62 patients (45 males and 17 females) with a primary intracranial GCT were retrospectively analyzed. Mean patient age was 18 years, and median follow-up was 41 months. The most common histological subtypes were germinoma (48.4%), followed by mixed GCT (27.4%), and teratoma (19.4%). In 23 patients (37.1%), disease onset occurred between 16 and 20 years. Germinomas and malignant non-germinomatous germ cell tumors were most prevalent in the pineal gland, suprasellar region, and basal ganglia, whereas teratomas dominated at other sites. Synchronous bifocal GCTs were found in six patients. Five-year overall survival (OS) rates according to a therapeutic classification proposed by Sawamura were 82.93%, 83.08%, and 64.71% in the good, intermediate, and poor prognosis groups, respectively (P = 0.2839). Five-year OSs in patients with normal tumor marker (alphaFP or betaHCG) and patients with elevated marker were 85.26% and 66.96%, respectively (P = 0.0568). Five of six patients with alpha-fetoprotein (alpha-FP) of >1,000 ng/ml succumbed to disease, whereas all five patients with a beta-human chorionic gonadotropin of >1,000 mIU/ml survived. Mixed GCTs are more common in Korea than in the West. Sawamura's classification of intracranial GCT may be a fine tool for stratifying patients' survival. Patients with elevated tumor marker levels may appear to have poorer OS independent of histology. In particular, high titers of alpha-FP seem to impact prognosis.
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Affiliation(s)
- Dakeun Lee
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea
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14
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Marshall GA, McMahon SK, Nicholls W, Pretorius CJ, Ungerer JPJ. Gonadotrophin-independent precocious puberty in an eight-year-old boy due to ectopic human chorionic gonadotrophin from the central nervous system. Ann Clin Biochem 2010; 47:271-4. [DOI: 10.1258/acb.2010.009267] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
We present the case of an eight-year-old boy with advanced isosexual precocity associated with an elevated serum total-beta human chorionic gonadotrophin (HCG) and markedly elevated serum total testosterone. Radiological investigation discovered a lesion in the left thalamus and no peripheral tumour. Serum:cerebrospinal fluid (CSF) HCG ratio was approximately 1:1, consistent with a central nervous system source of HCG, with thalamic germinoma strongly suspected. Consent was not obtained for biopsy of the lesion. The patient underwent multiagent chemotherapy with return of serum HCG to normal. We discuss mechanisms of HCG-mediated sexual precocity in both boys and girls and the importance of CSF HCG.
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Affiliation(s)
- G A Marshall
- Department of Chemical Pathology, Pathology Queensland
| | | | - W Nicholls
- Department of Paediatric Oncology, Royal Children's Hospital, Brisbane, QLD, 4029, Australia
| | - C J Pretorius
- Department of Chemical Pathology, Pathology Queensland
| | - J P J Ungerer
- Department of Chemical Pathology, Pathology Queensland
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15
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da Silva NS, Cappellano AM, Diez B, Cavalheiro S, Gardner S, Wisoff J, Kellie S, Parker R, Garvin J, Finlay J. Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study. Pediatr Blood Cancer 2010; 54:377-83. [PMID: 20063410 DOI: 10.1002/pbc.22381] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation. METHODS Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4-6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4-6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGbeta) and/or CSF HCGbeta <50 mIU/ml and high-risk (HR) biopsy-proven non-germinomatous malignant elements (MMGCT) or elevated serum/CSF alpha-fetoprotein and/or HCGbeta serum/CSF >50 mIU/ml. RESULTS Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. CONCLUSION These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT.
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Gutenberg A, Landek-Salgado M, Tzou SC, Lupi I, Geis A, Kimura H, Caturegli P. Autoimmune hypophysitis: expanding the differential diagnosis to CTLA-4 blockade. Expert Rev Endocrinol Metab 2009; 4:681-698. [PMID: 30780785 DOI: 10.1586/eem.09.37] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autoimmune hypophysitis is an increasingly recognized disorder that enters in the differential diagnosis of nonfunctioning pituitary masses. The differential diagnosis of these conditions is challenging because of similar clinical presentations and radiological signs. This review describes the essential features of hypophysitis and the other nonfunctioning pituitary masses. It also emphasizes a recently described feature of hypophysitis: its appearance with unexpectedly high frequency in patients receiving treatments that abrogate the function of cytotoxic T lymphocyte antigen 4.
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Affiliation(s)
- Angelika Gutenberg
- a Department of Neurosurgery, Georg-August University, Goettingen, Germany.
| | - Melissa Landek-Salgado
- b Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Shey-Cherng Tzou
- c Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Isabella Lupi
- d Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
| | - Abby Geis
- e Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Hiroaki Kimura
- f Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Patrizio Caturegli
- g Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
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Finlay J, da Silva NS, Lavey R, Bouffet E, Kellie SJ, Shaw E, Saran F, Matsutani M. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolution. Pediatr Blood Cancer 2008; 51:313-6. [PMID: 18421722 DOI: 10.1002/pbc.21555] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Jonathan Finlay
- The Neural Tumors Program and Radiation Oncology Program, Childrens Center for Cancer & Blood Diseases, Childrens Hospital Los Angeles, California 90027-6016, USA.
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18
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19
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Shim KW, Kim TG, Suh CO, Cho JH, Yoo CJ, Choi JU, Kim JH, Kim DS. Treatment failure in intracranial primary germinomas. Childs Nerv Syst 2007; 23:1155-61. [PMID: 17610071 DOI: 10.1007/s00381-007-0394-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2007] [Revised: 05/20/2007] [Indexed: 01/09/2023]
Abstract
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.
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Affiliation(s)
- Kyu-Won Shim
- Department of Neurosurgery, Brain Korea 21 Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, Seoul, South Korea
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20
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Ogino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara SI, Yamada T, Sugie C, Nomoto Y, Mimura M. CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys 2005; 62:803-8. [PMID: 15936563 DOI: 10.1016/j.ijrobp.2004.10.026] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2004] [Revised: 10/22/2004] [Accepted: 10/25/2004] [Indexed: 01/16/2023]
Abstract
PURPOSE The prognostic significance of human chorionic gonadotropin (HCG) level in central nervous system germinoma remains controversial. The purpose of this study was to compare clinical characteristics and prognosis of germinoma patients with normal and high HCG titers in the serum. METHODS AND MATERIALS We undertook a multi-institutional retrospective analysis of 103 patients with central nervous system germinoma whose serum HCG and/or beta-HCG level had been measured before treatment between 1984 and 2002. All patients had been treated with radiation therapy either alone (n = 66) or in combination with chemotherapy (n = 37) with a median dose of 47.8 Gy. RESULTS HCG and/or beta-HCG level in the serum was high in 39% of all patients. The proportion of HCG-producing tumors was higher in the lesions at the basal ganglia than in the lesions at the other sites. No correlation was found between tumor size and HCG level, but there seemed to be a weak correlation between size and beta-HCG. The 5- and 10-year survival rates were 96% and 94%, respectively, in both patient groups with normal and high HCG (p = 0.99). The 5- and 10-year relapse-free survival rates were 87% and 82%, respectively, in patients with normal HCG level and were both 87% in patients with high HCG (p = 0.74). Also, no other patient-, tumor-, or treatment-related factors seemed to influence the prognosis of the patients. CONCLUSION Serum HCG level does not seem to influence patient prognosis when treated with sufficient doses of radiation. Relationship between tumor size and site and HCG level should be investigated further.
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Affiliation(s)
- Hiroyuki Ogino
- Department of Radiology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
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21
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Abstract
Despite excellent long-term results for patients with germinoma treated with radiation therapy, the potential for late effects makes the treatment controversial. On the other hand, most patients with non-germinomatous tumors treated by conventional treatment with surgery and radiation therapy fail to survive longer than 3 years. After combination chemotherapy with cisplatin was confirmed to be effective in gonadal germ cell tumors, germ cell tumors of the brain became candidates for chemotherapy. The author reviews several prospective phase II studies that are being investigated to assess the effect of combination chemotherapy and radiation therapy for germ cell tumors. The aim of these studies is to reduce the volume and dose of radiation therapy for germinoma and prolong the survival of patients of non-germinomatous tumors. For germinoma, a trial with chemotherapy alone failed, with a high rate of recurrence, but Japanese and European trials with reduced-dose chemotherapy and a smaller volume of radiation therapy have resulted in high event-free survival (EFS) rates. Ongoing phase II studies with combined chemotherapy and radiation therapy for non-germinomatous tumors will result in a 5-year survival rate of greater than 50%, which is better than that achieved by radiation therapy alone.
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Affiliation(s)
- Masao Matsutani
- Department of Neurosurgery, Saitama Medical School, Saitama, Japan.
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Kanagaki M, Miki Y, Takahashi JA, Shibamoto Y, Takahashi T, Ueba T, Hashimoto N, Konishi J. MRI and CT findings of neurohypophyseal germinoma. Eur J Radiol 2004; 49:204-11. [PMID: 14962649 DOI: 10.1016/s0720-048x(03)00172-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2003] [Revised: 05/30/2003] [Accepted: 06/02/2003] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Magnetic resonance (MR) imaging and computed tomography (CT) findings of neurohypophyseal germinoma have not previously been described in detail. The purpose of the present study was to establish the spectrum of MR imaging and CT findings in neurohypophyseal germinomas. MATERIALS AND METHODS MR and CT images of 13 consecutive patients (seven males, six females; mean age: 15 years; range: 6-31 years) with neurohypophyseal germinoma were retrospectively analyzed. The diagnosis had been made either histologically (n=8) or clinically according to established criteria (n=5). All patients had been examined using MR imaging and CT before treatment. RESULTS On MR imaging, infundibular thickening (up to 16 mm) was observed in all 13 cases. Hyperintensity of the posterior pituitary on T1-weighted image was absent in all 13 cases (100%) and 12 of the 13 displayed central diabetes insipidus. Ten germinomas (77%) were isointense to cerebral cortex on T1-weighted image, but variable intensities were exhibited on T2-weighted image. MR images revealed intratumoral cysts in six cases (46%), most of which demonstrated intra-third ventricular extension. Eleven of the 13 cases (85%) revealed hyperdense solid components on unenhanced CT. Calcification was absent in all cases (100%). CONCLUSION Infundibular thickening, absence of the posterior pituitary high signal on T1-weighted image, lack of calcification and hyperdensity on unenhanced CT are common imaging features of neurohypophyseal germinoma.
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Affiliation(s)
- Mitsunori Kanagaki
- Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
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Ogawa K, Shikama N, Toita T, Nakamura K, Uno T, Onishi H, Itami J, Kakinohana Y, Kinjo T, Yoshii Y, Ito H, Murayama S. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int J Radiat Oncol Biol Phys 2004; 58:705-13. [PMID: 14967424 DOI: 10.1016/j.ijrobp.2003.07.001] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2003] [Revised: 07/24/2003] [Accepted: 07/29/2003] [Indexed: 12/13/2022]
Abstract
PURPOSE Optimal management of radiotherapy (RT) for intracranial germinoma remains controversial. This study was conducted to evaluate the long-term results of RT in patients with these tumors. METHODS AND MATERIALS The study group consisted of 126 patients with intracranial germinoma (50 patients with pathologically verified germinoma and 76 clinically diagnosed with germinoma by clinical and neuroradiologic signs) who were treated by RT alone between 1980 and 2001. The median age at diagnosis was 17 years (range, 2-47), and various radiation doses and treatment fields were used. Serum human chorionic gonadotropin (hCG) levels were elevated in 18 patients. The median follow-up of the 114 surviving patients was 122 months (range, 13-263). RESULTS The 10-year actuarial overall survival and cause-specific survival rate for all patients was 90% and 95%, respectively. The 10-year actuarial cause-specific survival rate for patients with and without elevated hCG levels was 94%. Relapses were noted in 10 patients, 7 of whom died of the disease. No in-field relapses at primary sites were observed in 72 patients treated with total doses of 40-50 Gy. The incidence of spinal relapses was 4% (2 of 56) for patients treated with spinal irradiation and 3% (2 of 70) for those without spinal irradiation. After a median 10-year follow-up, 54 (92%) of 59 patients with tumors not involving the neurohypophyseal region and 42 (76%) of 55 patients with tumors involving the neurohypophyseal region had Karnofsky performance status scores of 90-100%. With regard to school education and occupation, 54 (92%) of 59 patients with tumors not involving the neurohypophyseal region and 39 (71%) of 55 patients with tumors involving the neurohypophyseal region were attending school or undertaking occupations. Hormonal replacement therapy was required in 50 (44%) of 114 surviving patients before RT; only 4 patients (4%), all with neurohypophyseal tumors, required hormonal replacement therapy after RT. Clinically evident severe neurocognitive dysfunctions were documented in 10 patients before RT, and no patients treated with total doses of <55 Gy developed apparent neurocognitive dysfunctions or other complications after RT. CONCLUSION RT was a curative treatment for intracranial germinoma, and elevated serum hCG levels did not affect the prognosis of patients treated by RT alone. A total dose of 40-50 Gy to adequate treatment fields was effective in preventing intracranial relapse, and the incidence of spinal relapses was too low to warrant routine spinal irradiation. Karnofsky performance status scores, educational achievement, and the ability to work were generally good, particularly in patients with tumors that did not involve the neurohypophyseal region. Because most complications, such as hormonal deficiency and neurocognitive dysfunction, were documented before RT and newly diagnosed complications after RT were infrequent, the treatment toxicity faced by germinoma patients appears to be less than anticipated.
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Affiliation(s)
- Kazuhiko Ogawa
- Department of Radiology, University of the Ryukyus, Okinawa, Japan.
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Shin KH, Kim IH, Choe G. Impacts of elevated level of hCG in serum on clinical course and radiotherapy results in the histology-confirmed intracranial germinomas. Acta Oncol 2001; 40:98-101. [PMID: 11321670 DOI: 10.1080/028418601750071145] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The prognosis of intracranial germinoma producing the human chorionic gonadotropin (hCG) is controversial due to limited information. We undertook a retrospective analysis to determine whether this type of tumor has similar clinical course and prognosis to hCG non-secreting germinoma. Thirty-one histologically confirmed intracranial germinoma patients who had pretreatment hCG examination in serum/CSF were treated with radiotherapy between 1980 and 1996. hCG level was measured by immunoradioassay of beta subunit of hCG. Six patients had elevated serum hCG levels and were defined as having hCG secreting germinoma. All except three patients received craniospinal axis irradiation. The follow-up ranged from 19-175 months with a median of 63 months. hCG secreting germinoma accounted for 19% of intracranial germinoma cases. Elevated hCG levels ranged from 39-260 IU/l in serum. No difference was found between hCG non-secreting germinoma and hCG secreting germinoma in terms of patient or treatment characteristics. There was no recurrence among the six hCG secreting germinoma patients. The 5-year overall and disease-free survival rates were 96% for patients with hCG non-secreting germinomas and 100% for the patients with hCG secreting germinomas. The survival difference was not significant (p = 0.59). Our results suggest that elevated level of hCG did not result in any differences in the clinical characteristics or survival after radical radiotherapy in histologically confirmed intracranial germinoma.
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Affiliation(s)
- K H Shin
- Department of Therapeutic Radiology, Seoul National University College of Medicine, the Institute of Radiation Medicine, Medical Research Center, Korea
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Daido S, Namba K, Ono Y, Tamiya T, Ohmoto T. A Case Report of HCG-producing Germinoma in the Basal Ganglia with Precocious Puberty. ACTA ACUST UNITED AC 2001. [DOI: 10.7887/jcns.10.796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Shigeru Daido
- Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry
| | - Katsunari Namba
- Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry
| | - Yasuhiro Ono
- Department of Neurological Surgery, Okayama University Graduate School of Mdicine and Dentistry
| | - Takashi Tamiya
- Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry
| | - Takashi Ohmoto
- Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry
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