Elevation of hCG in CSF in pinealoblastoma: a pitfall rescued by pathological examination

Elevation of hCG in CSF in pinealoblastoma: a pitfall rescued by pathological examination | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Elevation of hCG in CSF in pinealoblastoma: a pitfall rescued by pathological examination François Bouille, Karima Mokhtari, Bertrand Mathon, Jérôme Alexandre Denis, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7261925/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted 7 You are reading this latest preprint version Abstract Human chorionic gonadotropin (hCG) is a hormone that may be abnormally secreted in several tumour types, including intracranial germ cell tumours. In pineal region tumors, hCG is a key tumor marker. In fact, mild elevation typically suggests a germinoma with syncytiotrophoblastic cells, whereas a markedly elevated level indicates a choriocarcinoma or a mixed germ cell tumor with trophoblastic differentiation. While histopathological confirmation remains the diagnostic gold standard, the anatomical situation of the pineal gland makes biopsy very challenging. In certain situations, diagnosis may therefore rely on a constellation of clinical, radiological, and biochemical findings, including cerebrospinal fluid (CSF) β-hCG levels. However, the differential diagnosis of pineal region tumours includes other primary neoplasms of the pineal parenchyma, which differ markedly in both prognosis and therapeutic management. Here, we report two cases of pineoblastoma with unexpectedly elevated CSF β-hCG levels, which might have led to a misdiagnosis of intracranial germinoma. These cases highlight the need for the development of novel, non-invasive biomarkers to improve the diagnostic accuracy of intracranial tumours. Pineoblastoma β-hCG Pineal region tumour Germinoma Figures Figure 1 Figure 2 Introduction Tumours of the pineal region represent less than 1% of all intracranial adult tumours in North America and Europe [ 15 ]. Despite an overlapping clinical presentation and sometimes a similar MRI features, different diagnoses must be considered. The most common tumours in this region are, in decreasing order of frequency, germ cell tumours, primary pineal parenchymal tumours (including pineoblastomas), and gliomas — each with distinct prognoses and treatment strategies [ 17 ]. In imaging studies, pineoblastomas typically present as poorly defined, irregular, and densely cellular masses. They may contain cysts or areas of necrosis, often spread through the cerebrospinal fluid (CSF), and show vivid, heterogeneous enhancement. Traditionally, they are characterized by calcifications scattered at the periphery, a feature they share with pineocytomas but which contrasts with pineal germinomas [ 8 ]. Pineal germinomas usually incorporate the pineal calcification rather than dispersing it. Histopathological examination remains the gold standard for establishing a definitive diagnosis, but biopsy is sometimes challenging due to the deep location of the pineal region [ 19 ]. The secretion of tumour markers — alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG) and its free β subunit (β-hCG) — is pragmatically accepted as sufficient for diagnosing a secreting germ cell tumour, when supported by a clinically and radiologically compatible case [ 9 ]. hCG is a hormone that may be secreted by syncytiotrophoblastic cells in germ cell tumours such as choriocarcinomas or germinomas [ 6 ]. When detected in the blood at levels above a certain threshold — typically above 50 IU/L — or in the CSF, the diagnosis of germ cell tumour can be established without a histopathological confirmation [ 18 ]. However, the hCG threshold that reliably supports a diagnosis of germinoma in the context of an intracerebral tumour remains controversial [ 5 , 13 ]. Here, we report two cases of Pineoblastoma with unexpectedly elevated hCG levels which could have led to the misdiagnosis of a germ cell tumour. Case #1 A 25-year-old female with no significant past medical history initially underwent a brain MRI for chronic tension-type headaches. Imaging revealed a tissular lesion of the pineal gland, with no associated mass effect on the surrounding brain parenchyma. A conservative approach with simple monitoring was recommended. Six months later, the patient was urgently admitted for signs of increased intracranial pressure, which had been progressively worsening for several months. A contrast-enhanced brain MRI confirmed the presence of the pineal enhancing mass, smaller than 2 cm in size, that exhibited restricted diffusion (indicating high cellularity), small cysts, and diffuse leptomeningeal enhancement in the posterior fossa (Fig. 1 ). On CT scan, no calcification was seen. No obstructive hydrocephalus was present. Spinal MRI further revealed extensive leptomeningeal spread to the cauda equina nerve roots. Initial lumbar puncture showed a lymphocytic meningitis with 20 white blood cells/mm³ (82% lymphocytes), a protein level of 2.29 g/L and a normoglycorrhachia of 0.91 mmol/L. She was initially treated as neuromeningeal tuberculosis (i.e., Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) and was then referred to the neuro-oncology department, due to the negativity of PCR for Mycobacterium tuberculosis and cultures, and the absence of clinical improvement under treatment. A second lumbar puncture revealed the following tumour markers in the CSF: hCG = 27 IU/L, free β-hCG = 1.97 IU/L (measured using B.R.A.H.M.S Free βhCG Kryptor, LOD = 0.16 IU/L), and AFP = 1.0 µg/L. Serum levels of hCG, free β-hCG and AFP were undetectable, making a peripheral source such as pregnancy or an ovarian trophoblastic tumor highly unlikely, and suggesting intrathecal secretion of intracranial origin. The diagnosis of intracranial germinoma was initially proposed. However, CSF cytology revealed abnormal cells expressing synaptophysin, raising suspicion for a pineal parenchymal tumour (Fig. 2A and B). A leptomeningeal open biopsy was subsequently performed and confirmed a primitive pineal parenchymal tumour (Fig. 2C-E). The gene panel analysis revealed a low-dynamic profile and did not identify variants in the genes DICER1, DROSHA, and KBTBD4. Methylome profiling supported the diagnosis of Pineoblastoma. We retrospectively analyzed NSE and Chromogranin A levels (B.R.A.H.M.S Kryptor Gold), which revealed cerebrospinal fluid/serum ratios of 7 and 45, respectively, supporting active intrathecal tumor production by a neuro-endocrine tumor. Case #2 A healthy 5-year-old girl with no personal or family medical history was admitted with a 7-day history of headaches and vomiting. Brain MRI revealed a T1 isointense tumour with heterogeneous gadolinium enhancement. Spinal MRI demonstrated diffuse leptomeningeal contrast enhancement throughout the spinal cord and nerve roots. A ventriculocisternostomy was performed for symptomatic relief. On postoperative day 5, the patient developed fever suggestive of meningitis and was empirically treated with Cefotaxime and Fosfomycin. CSF analysis revealed turbid fluid with a leukocyte count of 160/mm³ (82% neutrophils), elevated protein level (3.21 g/L), and hypoglycorrhachia (0.28 g/L). Hormonal evaluation showed an elevated free β-hCG level in the CSF (14 IU/L; Access Beckman assay), while AFP was undetectable (ECL Ortho technique). Neither marker was detectable in serum. As cytological analysis of the CSF was non-contributive, a stereotaxic biopsy of the pineal region was performed. Histopathological examination revealed a neoplasm expressing synaptophysin and neurofilaments, with a MIB-1 proliferation index of 50%. These findings established the diagnosis of Pineoblastoma with diffuse leptomeningeal spread. Discussion According to the World Health Organization (WHO) 2021 classification, intracranial malignant germ cell tumours (GCTs) are divided into secreting and non-secreting types based on tumour marker production. A marked increase in AFP indicates the presence of a yolk sac tumour component, while a significant rise in hCG reflects a syncytiotrophoblastic component. These findings are generally diagnostic of secreting intracranial GCTs without ambiguity. In contrast, pure germinomas are generally non-secreting but may exhibit low levels of β-hCG, likely due to the presence of syncytiotrophoblastic cells. Lastly, mature and immature teratomas, although part of the malignant GCT spectrum, are typically non-secreting unless associated with mixed histological components [ 9 , 16 ]. To our knowledge, our cases are the first reported in literature of pineoblastoma being misdiagnosed as germinomas due to moderately elevated hCG levels in the CSF. Hu et al. demonstrated a correlation between serum and CSF hCG levels in germinomas, but CSF measurement is considered more sensitive for diagnostic purposes [ 13 , 24 ]. It is generally accepted that a CSF β-hCG level > 50 IU/L should raise suspicion for choriocarcinoma, whereas detectable but lower levels may suggest a germinoma [ 3 , 10 ]. However, a lower threshold of 8.2 IU/L has also been shown to predict tumour type with excellent specificity [ 13 ]. As the normal β-hCG concentration in CSF is generally considered to be undetectable, the minimal threshold of β-hCG that should prompt consideration of germinoma remains controversial. In fact, in cases where biopsy is particularly high-risk, low-level β-hCG elevation can be considered sufficient to establish a diagnosis without histological confirmation [ 18 ]. Minimal values from 0.1 mIU/mL [ 21 ] to 6 mIU/mL [ 2 ] have been proposed, depending on the study location and assay used. A retrospective study by Zhang et al. tested serum β-hCG thresholds of 0.1 mIU/mL or 0.5 mIU/mL for the diagnosis of intracranial germinomas, although these resulted in false positive rates of 9.0% and 3.8%, respectively. This low threshold is difficult to establish, given that some germinomas lack a secreting component, leading to false negatives. Given the frequent discrepancies observed between β-hCG concentrations in serum and cerebrospinal fluid, parallel measurement in both compartments remains essential to ensure accurate interpretation [ 30 ]. Given the therapeutic implications, potential causes of false-positive hCG results should be carefully considered. For example, Rotmensch et al. reported a series of 12 women who received chemotherapy for suspected post-gestational choriocarcinoma based solely on elevated serum β-hCG, later found to be falsely elevated due to heterophile antibodies [ 25 ]. Numerous other causes of elevated hCG have been reported in the literature, most notably renal failure, but also, to a lesser extent, autoimmune diseases and hepatic failure [ 28 ]. In our first patient, drug-induced hepatocellular injury due to antituberculous therapy may have contributed to the hCG elevation. It is important to note that germ cell tumours are not the only intracranial tumours associated with increased serum and CSF hCG levels. Craniopharyngiomas have long been known to occasionally secrete hCG into the CSF [ 11 , 26 ]. Furthermore, several other intracranial tumours have been shown to produce hCG in their cystic components, including pituitary adenomas, arachnoid cysts, and pulmonary cancer metastases [ 12 ]. However, to our knowledge, hCG levels in the CSF have not been reported in these tumour types. Our cases underscore the need for reliable biological diagnostic criteria when evaluating suspected intracranial germinomas. Detection of placental alkaline phosphatase (PLAP) in the CSF has been proposed to differentiate germinomas from WHO grade 3 pineal parenchymal tumours [ 14 ]. PLAP, a membrane-bound trophoblastic protein, is already used in the workup of testicular germinomas. Several authors have demonstrated its good sensitivity and specificity for intracranial germinomas, including non-secreting tumours [ 4 , 22 ]. Aihara et al. even proposed a diagnostic algorithm incorporating PLAP and hCG to differentiate between various intracranial germ cell tumours [ 1 ]. Nevertheless, false-negative results have been reported with PLAP as well [ 23 ]. In our case, we measured chromogranin A and neuron-specific enolase (NSE), which are typical markers of neuroendocrine tumors and may also provide diagnostic insights in this context. More recently, a study analyzed circulating DNA (ctDNA) from CSF at the time of diagnosis in 19 pediatric patients with intracranial germ cell tumours (including 14 germinomas). Tumour DNA was detected in 17 out of 19 patients, including 8 with negative β-hCG levels [ 20 ]. Another study compared the expression of 12 microRNAs (miRNAs) in five patients with intracranial germinomas and three controls (two healthy individuals and one patient with chronic lymphocytic leukemia). Several miRNAs were significantly elevated in both the blood and CSF of germinoma patients. This elevation occurred even in cases with undetectable hCG [ 27 ]. In another pediatric study including 12 germinoma patients and 27 controls (17 with primary pineal parenchymal tumours), 3 out of 2652 plasma miRNAs were significantly overexpressed in germinoma patients. However, prospective studies are needed to further evaluate these findings [ 7 ]. Finally, Yu et al. proposed an integrative diagnostic model combining clinical, imaging, and biological parameters such as β-hCG to differentiate primary pineal tumours from intracranial germ cell tumours. This model was based on a cohort of 53 patients with germ cell tumours and 37 with pineal parenchymal tumours. The model showed excellent diagnostic performance in distinguishing pineal from germ cell tumours (AUC = 0.885; 95% CI: 0.732–1.000), and germinomas from non-germinomatous germ cell tumours (AUC = 0.926; 95% CI: 0.828–1.000). Interestingly, two pineal parenchymal tumours in this cohort exhibited abnormal hCG levels [ 29 ]. Conclusion These cases illustrate that low levels of hCG should not be used as a standalone diagnostic marker. They reinforce the critical role of brain biopsy in establishing a definitive diagnosis in complex cases, to avoid inappropriate treatments in patients with pineal lesions. They also underscore the need to develop novel non-invasive diagnostic tools for pineal region tumours. In situations where brain biopsy is not feasible, diagnostic assessment should rely on a combination of imaging features, cytological markers and new biological markers including miRNA and potentially ctDNA. Abbreviations hCG: Human Chorionic Gonadotropin miRNA: MicroRNA ctDNA: Circulating Tumour DNA PLAP: Placental Alkaline Phosphatase WHO: World Health Organization CSF: Cerebrospinal Fluid AUC: Area Under the Curve AFP: Alpha-Fetoprotein Declarations Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki and complied with the ethical guidelines of the Assistance Publique – Hôpitaux de Paris (AP-HP) and Institut Curie. Consent for publication Both patients provided written informed consent for the anonymous publication of their health data, after being informed of the scientific purpose of the publication. Competing interests The authors declare no competing interests. Funding The authors declare that they received no financial support for the research, authorship, or publication of this article Acknowledgements We would like to thank the two patients for granting permission to publish the data presented in this article. Author contributions François Bouille: manuscript writing, data analysis Karima Mokhtari: data acquisition, manuscript review Bertrand Mathon: data acquisition, manuscript review Jérôme Denis: data acquisition, manuscript review Lucia Nichelli: data acquisition, manuscript review François Doz: data acquisition, manuscript review Alice Leprince-Laurenge: data analysis, manuscript review Ahmed Idbaih: data analysis, manuscript review References Aihara Y, Watanabe S, Amano K, Komatsu K, Chiba K, Imanaka K, et al. (2019) Placental alkaline phosphatase levels in cerebrospinal fluid can have a decisive role in the differential diagnosis of intracranial germ cell tumors. J Neurosurg 131:687–694. https://doi.org/10.3171/2018.3.JNS172520 Allen J, Chacko J, Donahue B, Dhall G, Kretschmar C, Jakacki R, et al. (2012) Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer 59:1180–1182. https://doi.org/10.1002/pbc.24097 Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garrè ML, et al. (2013) SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma. Neuro Oncol 15:788–796. https://doi.org/10.1093/neuonc/not019 Chiba K, Aihara Y, Kawamata T (2021) Precise detection of the germinomatous component of intracranial germ cell tumors of the basal ganglia and thalamus using placental alkaline phosphatase in cerebrospinal fluid. J Neurooncol 152:405–413. https://doi.org/10.1007/s11060-021-03715-9 Cohen D, Litofsky NS (2023) Diagnosis and management of pineal germinoma: from eye to brain. Endocrinol Bull 15:45–61. https://doi.org/10.2147/EB.S389631 Diezi M, Pizer B, Murray MJ (2024) Overview of current European practice for the management of patients with intracranial germ cell tumours. EJC Paediatr Oncol 3:100146. https://doi.org/10.1016/j.ejcped.2024.100146 Fakhry M, Elayadi M, Elzayat MG, Samir O, Maher E, Taha H, et al. (2024) Plasma miRNA expression profile in pediatric pineal pure germinomas. Front Oncol 14:1219796. https://doi.org/10.3389/fonc.2024.1219796 Favero G, Bonomini F, Rezzani R (2021) Pineal gland tumors: a review. Cancers (Basel) 13:1547. https://doi.org/10.3390/cancers13071547 Frappaz D, Dhall G, Murray MJ, Goldman S, Faure Conter C, Allen J, et al. (2022) EANO, SNO and EURACAN consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults. Neuro Oncol 24:516–527. https://doi.org/10.1093/neuonc/noab252 González-Sánchez V, Moreno-Pérez O, Pellicer PS, Sánchez-Ortiga R, Guerra RA, Dot MM, et al. (2011) Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas. Ann Clin Biochem 48:433–437. https://doi.org/10.1258/acb.2010.010074 Gu W, Gu W, Gu Y, Li J, Yang G, Guo Q, et al. (2018) A craniopharyngioma associated with elevated cerebrospinal fluid HCG concentrations misdiagnosed as a germinoma. Front Neurol 9:449. https://doi.org/10.3389/fneur.2018.00449 Honegger J, Mann K, Thierauf P, Zrinzo A, Fahlbusch R (1995) Human chorionic gonadotrophin immunoactivity in cystic intracranial tumours. Clin Endocrinol (Oxf) 42:235–241. https://doi.org/10.1111/j.1365-2265.1995.tb01870.x Hu M, Guan H, Lau CC, Terashima K, Jin Z, Cui L, et al. (2016) An update on the clinical diagnostic value of β-hCG and αFP for intracranial germ cell tumors. Eur J Med Res 21:10. https://doi.org/10.1186/s40001-016-0204-2 Ito K, Aihara Y, Chiba K, Oda Y, Kawamata T (2024) A case of a pineal parenchymal tumor of intermediate differentiation with bifocal lesions differentiated by negative placental alkaline phosphatase in the spinal fluid. Childs Nerv Syst 40:2935–2939. https://doi.org/10.1007/s00381-024-06429-1 Lombardi G, Poliani PL, Manara R, Berhouma M, Minniti G, Tabouret E, et al. (2022) Diagnosis and treatment of pineal region tumors in adults: a EURACAN overview. Cancers (Basel) 14:3646. https://doi.org/10.3390/cancers14153646 Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231–1251. https://doi.org/10.1093/neuonc/noab106 Mottolese C, Szathmari A, Beuriat PA (2015) Incidence of pineal tumours: a review of the literature. Neurochirurgie 61:65–69. https://doi.org/10.1016/j.neuchi.2014.01.005 Murray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC (2015) Consensus on the management of intracranial germ-cell tumours. Lancet Oncol 16:e470–e477. https://doi.org/10.1016/S1470-2045(15)00244-2 Nakamura H, Takami H, Yanagisawa T, Kumabe T, Fujimaki T, Arakawa Y, et al. (2022) The Japan Society for Neuro-Oncology guideline on the diagnosis and treatment of central nervous system germ cell tumors. Neuro Oncol 24:503–515. https://doi.org/10.1093/neuonc/noab242 Nakano Y, Burns I, Nobre L, Siddaway R, Rana M, Nesvick C, et al. (2024) High detection rate of circulating-tumor DNA from cerebrospinal fluid of children with central nervous system germ cell tumors. Acta Neuropathol Commun 12:178. https://doi.org/10.1186/s40478-024-01886-w Ogino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara SI, Yamada T, et al. (2005) CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys 62:803–808. https://doi.org/10.1016/j.ijrobp.2004.10.026 Okamoto M, Yamaguchi S, Ishi Y, Motegi H, Mori T, Hashimoto T, et al. (2021) Diagnostic capability of cerebrospinal fluid-placental alkaline phosphatase value in intracranial germ cell tumor. Oncology 99:23–31. https://doi.org/10.1159/000509395 Oki S, Yamaguchi S, Okamoto M, Ishi Y, Kanno-Okada H, Takakuwa E, et al. (2025) Mature teratoma with a germinoma component presenting with undetectable placental alkaline phosphatase in cerebrospinal fluid: illustrative case. J Neurosurg Case Lessons 9:CASE24588. https://doi.org/10.3171/CASE24588 Qaddoumi I, Sane M, Li S, Kocak M, Pai-Panandiker A, Harreld J, et al. (2012) Diagnostic utility and correlation of tumor markers in the serum and cerebrospinal fluid of children with intracranial germ cell tumors. Childs Nerv Syst 28:1017–1024. https://doi.org/10.1007/s00381-012-1762-4 Rotmensch S, Cole LA (2000) False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 355:712–715. https://doi.org/10.1016/S0140-6736(00)01324-6 Saleh U, Lim LH, Ismail I, Wahab NA (2021) Misdiagnosis of elevation of β-hCG in cystic craniopharyngioma: illustrative case. J Neurosurg Case Lessons 1:CASE2025. https://doi.org/10.3171/CASE2025 Schönberger S, Mohseni MM, Ellinger J, Tran GVQ, Becker M, Claviez A, et al. (2023) MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors. J Cancer Res Clin Oncol 149:791–802. https://doi.org/10.1007/s00432-022-03915-4 Trapé J, Fernández-Galán E, Auge JM, Carbonell-Prat M, Filella X, Miró-Cañís S, et al. (2024) Factors influencing blood tumor marker concentrations in the absence of neoplasia. Tumour Biol 46:S35–S63. https://doi.org/10.3233/TUB-220023 Yu Y, Lu X, Yao Y, Xie Y, Ren Y, Chen L, et al. (2023) A 2-step prediction model for diagnosis of germinomas in the pineal region. Neurooncol Adv 5:vdad094. https://doi.org/10.1093/noajnl/vdad094 Zhang H, Zhang P, Fan J, Qiu B, Pan J, Zhang X, et al. (2016) Determining an optimal cutoff of serum β-human chorionic gonadotropin for assisting the diagnosis of intracranial germinomas. PLoS One 11:e0147023. https://doi.org/10.1371/journal.pone.0147023 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 21 Nov, 2025 Read the published version in Acta Neuropathologica Communications → Version 1 posted Editorial decision: Accepted 07 Oct, 2025 Reviews received at journal 29 Sep, 2025 Reviewers agreed at journal 12 Sep, 2025 Reviewers invited by journal 18 Aug, 2025 Editor assigned by journal 08 Aug, 2025 Submission checks completed at journal 08 Aug, 2025 First submitted to journal 31 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":true,"prefix":"","firstName":"François","middleName":"","lastName":"Bouille","suffix":""},{"id":505479063,"identity":"da8011e4-42d2-4ee5-940e-defabb068bf7","order_by":1,"name":"Karima Mokhtari","email":"","orcid":"","institution":"Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":false,"prefix":"","firstName":"Karima","middleName":"","lastName":"Mokhtari","suffix":""},{"id":505479065,"identity":"63169c90-574c-4b1e-beb1-4a4548dbc6cd","order_by":2,"name":"Bertrand Mathon","email":"","orcid":"","institution":"Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":false,"prefix":"","firstName":"Bertrand","middleName":"","lastName":"Mathon","suffix":""},{"id":505479066,"identity":"e065d244-77d0-4c20-a2ce-2bbb35ab8065","order_by":3,"name":"Jérôme Alexandre Denis","email":"","orcid":"","institution":"Sorbonne Université, INSERM UMR_S 938, Centre de Recherche Saint-Antoine (CRSA), APHP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Oncobiologie Cellulaire et Moléculaire","correspondingAuthor":false,"prefix":"","firstName":"Jérôme","middleName":"Alexandre","lastName":"Denis","suffix":""},{"id":505479068,"identity":"db849e38-2385-4b91-abb4-1cdc8d50de40","order_by":4,"name":"Lucia Nichelli","email":"","orcid":"","institution":"Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Nichelli","suffix":""},{"id":505479071,"identity":"9e117304-cc4f-4810-be7a-f5033a4e6539","order_by":5,"name":"Ahmed Idbaih","email":"","orcid":"","institution":"Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Idbaih","suffix":""},{"id":505479072,"identity":"80dbcba9-9211-43ad-acbb-867fbde647fd","order_by":6,"name":"François Doz","email":"","orcid":"","institution":"University Paris Cité and Institut Curie","correspondingAuthor":false,"prefix":"","firstName":"François","middleName":"","lastName":"Doz","suffix":""},{"id":505479074,"identity":"5052e9c0-650d-4dff-8ad2-c73a9800abc0","order_by":7,"name":"Alice Laurenge","email":"","orcid":"","institution":"Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix","correspondingAuthor":false,"prefix":"","firstName":"Alice","middleName":"","lastName":"Laurenge","suffix":""}],"badges":[],"createdAt":"2025-07-31 11:53:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7261925/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7261925/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40478-025-02148-z","type":"published","date":"2025-11-21T15:59:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89987881,"identity":"60196041-de57-4453-bd2a-9c7ecc54fd26","added_by":"auto","created_at":"2025-08-27 07:02:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1169939,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7261925/v1/dd4d264b4e9a49df2e45f287.png"},{"id":89987883,"identity":"e2d3e3ba-9b71-429f-b115-196da8834edc","added_by":"auto","created_at":"2025-08-27 07:02:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4978904,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7261925/v1/4cac213e72eec7420ac639e1.png"},{"id":96650264,"identity":"7db1f662-75f0-46bc-ab1d-68ef80d53824","added_by":"auto","created_at":"2025-11-24 16:10:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":9452462,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7261925/v1/da7e0e20-cc7f-4821-88d6-d48f5ffa85d7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevation of hCG in CSF in pinealoblastoma: a pitfall rescued by pathological examination","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTumours of the pineal region represent less than 1% of all intracranial adult tumours in North America and Europe [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Despite an overlapping clinical presentation and sometimes a similar MRI features, different diagnoses must be considered. The most common tumours in this region are, in decreasing order of frequency, germ cell tumours, primary pineal parenchymal tumours (including pineoblastomas), and gliomas \u0026mdash; each with distinct prognoses and treatment strategies [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In imaging studies, pineoblastomas typically present as poorly defined, irregular, and densely cellular masses. They may contain cysts or areas of necrosis, often spread through the cerebrospinal fluid (CSF), and show vivid, heterogeneous enhancement. Traditionally, they are characterized by calcifications scattered at the periphery, a feature they share with pineocytomas but which contrasts with pineal germinomas [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Pineal germinomas usually incorporate the pineal calcification rather than dispersing it. Histopathological examination remains the gold standard for establishing a definitive diagnosis, but biopsy is sometimes challenging due to the deep location of the pineal region [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe secretion of tumour markers \u0026mdash; alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG) and its free β subunit (β-hCG) \u0026mdash; is pragmatically accepted as sufficient for diagnosing a secreting germ cell tumour, when supported by a clinically and radiologically compatible case [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. hCG is a hormone that may be secreted by syncytiotrophoblastic cells in germ cell tumours such as choriocarcinomas or germinomas [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. When detected in the blood at levels above a certain threshold \u0026mdash; typically above 50 IU/L \u0026mdash; or in the CSF, the diagnosis of germ cell tumour can be established without a histopathological confirmation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, the hCG threshold that reliably supports a diagnosis of germinoma in the context of an intracerebral tumour remains controversial [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHere, we report two cases of Pineoblastoma with unexpectedly elevated hCG levels which could have led to the misdiagnosis of a germ cell tumour.\u003c/p\u003e"},{"header":"Case #1","content":"\u003cp\u003eA 25-year-old female with no significant past medical history initially underwent a brain MRI for chronic tension-type headaches. Imaging revealed a tissular lesion of the pineal gland, with no associated mass effect on the surrounding brain parenchyma. A conservative approach with simple monitoring was recommended.\u003c/p\u003e\u003cp\u003eSix months later, the patient was urgently admitted for signs of increased intracranial pressure, which had been progressively worsening for several months. A contrast-enhanced brain MRI confirmed the presence of the pineal enhancing mass, smaller than 2 cm in size, that exhibited restricted diffusion (indicating high cellularity), small cysts, and diffuse leptomeningeal enhancement in the posterior fossa (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). On CT scan, no calcification was seen. No obstructive hydrocephalus was present. Spinal MRI further revealed extensive leptomeningeal spread to the cauda equina nerve roots. Initial lumbar puncture showed a lymphocytic meningitis with 20 white blood cells/mm\u0026sup3; (82% lymphocytes), a protein level of 2.29 g/L and a normoglycorrhachia of 0.91 mmol/L. She was initially treated as neuromeningeal tuberculosis (i.e., Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol) and was then referred to the neuro-oncology department, due to the negativity of PCR for Mycobacterium tuberculosis and cultures, and the absence of clinical improvement under treatment. A second lumbar puncture revealed the following tumour markers in the CSF: hCG\u0026thinsp;=\u0026thinsp;27 IU/L, free β-hCG\u0026thinsp;=\u0026thinsp;1.97 IU/L (measured using B.R.A.H.M.S Free βhCG Kryptor, LOD\u0026thinsp;=\u0026thinsp;0.16 IU/L), and AFP\u0026thinsp;=\u0026thinsp;1.0 \u0026micro;g/L. Serum levels of hCG, free β-hCG and AFP were undetectable, making a peripheral source such as pregnancy or an ovarian trophoblastic tumor highly unlikely, and suggesting intrathecal secretion of intracranial origin. The diagnosis of intracranial germinoma was initially proposed. However, CSF cytology revealed abnormal cells expressing synaptophysin, raising suspicion for a pineal parenchymal tumour (Fig.\u0026nbsp;2A and B). A leptomeningeal open biopsy was subsequently performed and confirmed a primitive pineal parenchymal tumour (Fig.\u0026nbsp;2C-E). The gene panel analysis revealed a low-dynamic profile and did not identify variants in the genes DICER1, DROSHA, and KBTBD4. Methylome profiling supported the diagnosis of Pineoblastoma. We retrospectively analyzed NSE and Chromogranin A levels (B.R.A.H.M.S Kryptor Gold), which revealed cerebrospinal fluid/serum ratios of 7 and 45, respectively, supporting active intrathecal tumor production by a neuro-endocrine tumor.\u003c/p\u003e"},{"header":"Case #2","content":"\u003cp\u003eA healthy 5-year-old girl with no personal or family medical history was admitted with a 7-day history of headaches and vomiting. Brain MRI revealed a T1 isointense tumour with heterogeneous gadolinium enhancement. Spinal MRI demonstrated diffuse leptomeningeal contrast enhancement throughout the spinal cord and nerve roots. A ventriculocisternostomy was performed for symptomatic relief. On postoperative day 5, the patient developed fever suggestive of meningitis and was empirically treated with Cefotaxime and Fosfomycin. CSF analysis revealed turbid fluid with a leukocyte count of 160/mm\u0026sup3; (82% neutrophils), elevated protein level (3.21 g/L), and hypoglycorrhachia (0.28 g/L). Hormonal evaluation showed an elevated free β-hCG level in the CSF (14 IU/L; Access Beckman assay), while AFP was undetectable (ECL Ortho technique). Neither marker was detectable in serum. As cytological analysis of the CSF was non-contributive, a stereotaxic biopsy of the pineal region was performed. Histopathological examination revealed a neoplasm expressing synaptophysin and neurofilaments, with a MIB-1 proliferation index of 50%. These findings established the diagnosis of Pineoblastoma with diffuse leptomeningeal spread.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to the World Health Organization (WHO) 2021 classification, intracranial malignant germ cell tumours (GCTs) are divided into secreting and non-secreting types based on tumour marker production. A marked increase in AFP indicates the presence of a yolk sac tumour component, while a significant rise in hCG reflects a syncytiotrophoblastic component. These findings are generally diagnostic of secreting intracranial GCTs without ambiguity. In contrast, pure germinomas are generally non-secreting but may exhibit low levels of β-hCG, likely due to the presence of syncytiotrophoblastic cells. Lastly, mature and immature teratomas, although part of the malignant GCT spectrum, are typically non-secreting unless associated with mixed histological components [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. To our knowledge, our cases are the first reported in literature of pineoblastoma being misdiagnosed as germinomas due to moderately elevated hCG levels in the CSF.\u003c/p\u003e\u003cp\u003eHu et al. demonstrated a correlation between serum and CSF hCG levels in germinomas, but CSF measurement is considered more sensitive for diagnostic purposes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It is generally accepted that a CSF β-hCG level\u0026thinsp;\u0026gt;\u0026thinsp;50 IU/L should raise suspicion for choriocarcinoma, whereas detectable but lower levels may suggest a germinoma [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, a lower threshold of 8.2 IU/L has also been shown to predict tumour type with excellent specificity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAs the normal β-hCG concentration in CSF is generally considered to be undetectable, the minimal threshold of β-hCG that should prompt consideration of germinoma remains controversial. In fact, in cases where biopsy is particularly high-risk, low-level β-hCG elevation can be considered sufficient to establish a diagnosis without histological confirmation [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Minimal values from 0.1 mIU/mL [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] to 6 mIU/mL [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] have been proposed, depending on the study location and assay used. A retrospective study by Zhang et al. tested serum β-hCG thresholds of 0.1 mIU/mL or 0.5 mIU/mL for the diagnosis of intracranial germinomas, although these resulted in false positive rates of 9.0% and 3.8%, respectively. This low threshold is difficult to establish, given that some germinomas lack a secreting component, leading to false negatives. Given the frequent discrepancies observed between β-hCG concentrations in serum and cerebrospinal fluid, parallel measurement in both compartments remains essential to ensure accurate interpretation [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGiven the therapeutic implications, potential causes of false-positive hCG results should be carefully considered. For example, Rotmensch et al. reported a series of 12 women who received chemotherapy for suspected post-gestational choriocarcinoma based solely on elevated serum β-hCG, later found to be falsely elevated due to heterophile antibodies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Numerous other causes of elevated hCG have been reported in the literature, most notably renal failure, but also, to a lesser extent, autoimmune diseases and hepatic failure [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In our first patient, drug-induced hepatocellular injury due to antituberculous therapy may have contributed to the hCG elevation.\u003c/p\u003e\u003cp\u003eIt is important to note that germ cell tumours are not the only intracranial tumours associated with increased serum and CSF hCG levels. Craniopharyngiomas have long been known to occasionally secrete hCG into the CSF [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, several other intracranial tumours have been shown to produce hCG in their cystic components, including pituitary adenomas, arachnoid cysts, and pulmonary cancer metastases [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, to our knowledge, hCG levels in the CSF have not been reported in these tumour types.\u003c/p\u003e\u003cp\u003eOur cases underscore the need for reliable biological diagnostic criteria when evaluating suspected intracranial germinomas. Detection of placental alkaline phosphatase (PLAP) in the CSF has been proposed to differentiate germinomas from WHO grade 3 pineal parenchymal tumours [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. PLAP, a membrane-bound trophoblastic protein, is already used in the workup of testicular germinomas. Several authors have demonstrated its good sensitivity and specificity for intracranial germinomas, including non-secreting tumours [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Aihara et al. even proposed a diagnostic algorithm incorporating PLAP and hCG to differentiate between various intracranial germ cell tumours [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Nevertheless, false-negative results have been reported with PLAP as well [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In our case, we measured chromogranin A and neuron-specific enolase (NSE), which are typical markers of neuroendocrine tumors and may also provide diagnostic insights in this context.\u003c/p\u003e\u003cp\u003eMore recently, a study analyzed circulating DNA (ctDNA) from CSF at the time of diagnosis in 19 pediatric patients with intracranial germ cell tumours (including 14 germinomas). Tumour DNA was detected in 17 out of 19 patients, including 8 with negative β-hCG levels [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Another study compared the expression of 12 microRNAs (miRNAs) in five patients with intracranial germinomas and three controls (two healthy individuals and one patient with chronic lymphocytic leukemia). Several miRNAs were significantly elevated in both the blood and CSF of germinoma patients. This elevation occurred even in cases with undetectable hCG [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In another pediatric study including 12 germinoma patients and 27 controls (17 with primary pineal parenchymal tumours), 3 out of 2652 plasma miRNAs were significantly overexpressed in germinoma patients. However, prospective studies are needed to further evaluate these findings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFinally, Yu et al. proposed an integrative diagnostic model combining clinical, imaging, and biological parameters such as β-hCG to differentiate primary pineal tumours from intracranial germ cell tumours. This model was based on a cohort of 53 patients with germ cell tumours and 37 with pineal parenchymal tumours. The model showed excellent diagnostic performance in distinguishing pineal from germ cell tumours (AUC\u0026thinsp;=\u0026thinsp;0.885; 95% CI: 0.732\u0026ndash;1.000), and germinomas from non-germinomatous germ cell tumours (AUC\u0026thinsp;=\u0026thinsp;0.926; 95% CI: 0.828\u0026ndash;1.000). Interestingly, two pineal parenchymal tumours in this cohort exhibited abnormal hCG levels [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThese cases illustrate that low levels of hCG should not be used as a standalone diagnostic marker. They reinforce the critical role of brain biopsy in establishing a definitive diagnosis in complex cases, to avoid inappropriate treatments in patients with pineal lesions. They also underscore the need to develop novel non-invasive diagnostic tools for pineal region tumours. In situations where brain biopsy is not feasible, diagnostic assessment should rely on a combination of imaging features, cytological markers and new biological markers including miRNA and potentially ctDNA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ehCG: Human Chorionic Gonadotropin\u003c/p\u003e\n\u003cp\u003emiRNA: MicroRNA\u003c/p\u003e\n\u003cp\u003ectDNA: Circulating Tumour DNA\u003c/p\u003e\n\u003cp\u003ePLAP: Placental Alkaline Phosphatase\u003c/p\u003e\n\u003cp\u003eWHO: World Health Organization\u003c/p\u003e\n\u003cp\u003eCSF: Cerebrospinal Fluid\u003c/p\u003e\n\u003cp\u003eAUC: Area Under the Curve\u003c/p\u003e\n\u003cp\u003eAFP: Alpha-Fetoprotein\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and complied with the ethical guidelines of the Assistance Publique \u0026ndash; H\u0026ocirc;pitaux de Paris (AP-HP) and Institut Curie.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003cbr\u003eBoth patients provided written informed consent for the anonymous publication of their health data, after being informed of the scientific purpose of the publication.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003cbr\u003e\u0026nbsp;The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003cbr\u003e\u0026nbsp;The authors declare that they received no financial support for the research, authorship, or publication of this article\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003cbr\u003e\u0026nbsp;We would like to thank the two patients for granting permission to publish the data presented in this article.\u003c/p\u003e\n\u003ch3\u003eAuthor contributions\u003c/h3\u003e\n\u003cp\u003eFran\u0026ccedil;ois Bouille: manuscript writing, data analysis\u003cbr\u003e\u0026nbsp;Karima Mokhtari: data acquisition, manuscript review\u003cbr\u003e\u0026nbsp;Bertrand Mathon: data acquisition, manuscript review\u003cbr\u003e\u0026nbsp;J\u0026eacute;r\u0026ocirc;me Denis: data acquisition, manuscript review\u003cbr\u003e\u0026nbsp;Lucia Nichelli: data acquisition, manuscript review\u003cbr\u003e\u0026nbsp;Fran\u0026ccedil;ois Doz: data acquisition, manuscript review\u003cbr\u003e\u0026nbsp;Alice Leprince-Laurenge: data analysis, manuscript review\u003cbr\u003e\u0026nbsp;Ahmed Idbaih: data analysis, manuscript review\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAihara Y, Watanabe S, Amano K, Komatsu K, Chiba K, Imanaka K, et al. (2019) Placental alkaline phosphatase levels in cerebrospinal fluid can have a decisive role in the differential diagnosis of intracranial germ cell tumors. J Neurosurg 131:687\u0026ndash;694. https://doi.org/10.3171/2018.3.JNS172520\u003c/li\u003e\n\u003cli\u003eAllen J, Chacko J, Donahue B, Dhall G, Kretschmar C, Jakacki R, et al. (2012) Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr Blood Cancer 59:1180\u0026ndash;1182. https://doi.org/10.1002/pbc.24097\u003c/li\u003e\n\u003cli\u003eCalaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garr\u0026egrave; ML, et al. (2013) SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma. Neuro Oncol 15:788\u0026ndash;796. https://doi.org/10.1093/neuonc/not019\u003c/li\u003e\n\u003cli\u003eChiba K, Aihara Y, Kawamata T (2021) Precise detection of the germinomatous component of intracranial germ cell tumors of the basal ganglia and thalamus using placental alkaline phosphatase in cerebrospinal fluid. J Neurooncol 152:405\u0026ndash;413. https://doi.org/10.1007/s11060-021-03715-9\u003c/li\u003e\n\u003cli\u003eCohen D, Litofsky NS (2023) Diagnosis and management of pineal germinoma: from eye to brain. Endocrinol Bull 15:45\u0026ndash;61. https://doi.org/10.2147/EB.S389631\u003c/li\u003e\n\u003cli\u003eDiezi M, Pizer B, Murray MJ (2024) Overview of current European practice for the management of patients with intracranial germ cell tumours. EJC Paediatr Oncol 3:100146. https://doi.org/10.1016/j.ejcped.2024.100146\u003c/li\u003e\n\u003cli\u003eFakhry M, Elayadi M, Elzayat MG, Samir O, Maher E, Taha H, et al. (2024) Plasma miRNA expression profile in pediatric pineal pure germinomas. Front Oncol 14:1219796. https://doi.org/10.3389/fonc.2024.1219796\u003c/li\u003e\n\u003cli\u003eFavero G, Bonomini F, Rezzani R (2021) Pineal gland tumors: a review. Cancers (Basel) 13:1547. https://doi.org/10.3390/cancers13071547\u003c/li\u003e\n\u003cli\u003eFrappaz D, Dhall G, Murray MJ, Goldman S, Faure Conter C, Allen J, et al. (2022) EANO, SNO and EURACAN consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults. Neuro Oncol 24:516\u0026ndash;527. https://doi.org/10.1093/neuonc/noab252\u003c/li\u003e\n\u003cli\u003eGonz\u0026aacute;lez-S\u0026aacute;nchez V, Moreno-P\u0026eacute;rez O, Pellicer PS, S\u0026aacute;nchez-Ortiga R, Guerra RA, Dot MM, et al. (2011) Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas. Ann Clin Biochem 48:433\u0026ndash;437. https://doi.org/10.1258/acb.2010.010074\u003c/li\u003e\n\u003cli\u003eGu W, Gu W, Gu Y, Li J, Yang G, Guo Q, et al. (2018) A craniopharyngioma associated with elevated cerebrospinal fluid HCG concentrations misdiagnosed as a germinoma. Front Neurol 9:449. https://doi.org/10.3389/fneur.2018.00449\u003c/li\u003e\n\u003cli\u003eHonegger J, Mann K, Thierauf P, Zrinzo A, Fahlbusch R (1995) Human chorionic gonadotrophin immunoactivity in cystic intracranial tumours. Clin Endocrinol (Oxf) 42:235\u0026ndash;241. https://doi.org/10.1111/j.1365-2265.1995.tb01870.x\u003c/li\u003e\n\u003cli\u003eHu M, Guan H, Lau CC, Terashima K, Jin Z, Cui L, et al. (2016) An update on the clinical diagnostic value of \u0026beta;-hCG and \u0026alpha;FP for intracranial germ cell tumors. Eur J Med Res 21:10. https://doi.org/10.1186/s40001-016-0204-2\u003c/li\u003e\n\u003cli\u003eIto K, Aihara Y, Chiba K, Oda Y, Kawamata T (2024) A case of a pineal parenchymal tumor of intermediate differentiation with bifocal lesions differentiated by negative placental alkaline phosphatase in the spinal fluid. Childs Nerv Syst 40:2935\u0026ndash;2939. https://doi.org/10.1007/s00381-024-06429-1\u003c/li\u003e\n\u003cli\u003eLombardi G, Poliani PL, Manara R, Berhouma M, Minniti G, Tabouret E, et al. (2022) Diagnosis and treatment of pineal region tumors in adults: a EURACAN overview. Cancers (Basel) 14:3646. https://doi.org/10.3390/cancers14153646\u003c/li\u003e\n\u003cli\u003eLouis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23:1231\u0026ndash;1251. https://doi.org/10.1093/neuonc/noab106\u003c/li\u003e\n\u003cli\u003eMottolese C, Szathmari A, Beuriat PA (2015) Incidence of pineal tumours: a review of the literature. Neurochirurgie 61:65\u0026ndash;69. https://doi.org/10.1016/j.neuchi.2014.01.005\u003c/li\u003e\n\u003cli\u003eMurray MJ, Bartels U, Nishikawa R, Fangusaro J, Matsutani M, Nicholson JC (2015) Consensus on the management of intracranial germ-cell tumours. Lancet Oncol 16:e470\u0026ndash;e477. https://doi.org/10.1016/S1470-2045(15)00244-2\u003c/li\u003e\n\u003cli\u003eNakamura H, Takami H, Yanagisawa T, Kumabe T, Fujimaki T, Arakawa Y, et al. (2022) The Japan Society for Neuro-Oncology guideline on the diagnosis and treatment of central nervous system germ cell tumors. Neuro Oncol 24:503\u0026ndash;515. https://doi.org/10.1093/neuonc/noab242\u003c/li\u003e\n\u003cli\u003eNakano Y, Burns I, Nobre L, Siddaway R, Rana M, Nesvick C, et al. (2024) High detection rate of circulating-tumor DNA from cerebrospinal fluid of children with central nervous system germ cell tumors. Acta Neuropathol Commun 12:178. https://doi.org/10.1186/s40478-024-01886-w\u003c/li\u003e\n\u003cli\u003eOgino H, Shibamoto Y, Takanaka T, Suzuki K, Ishihara SI, Yamada T, et al. (2005) CNS germinoma with elevated serum human chorionic gonadotropin level: clinical characteristics and treatment outcome. Int J Radiat Oncol Biol Phys 62:803\u0026ndash;808. https://doi.org/10.1016/j.ijrobp.2004.10.026\u003c/li\u003e\n\u003cli\u003eOkamoto M, Yamaguchi S, Ishi Y, Motegi H, Mori T, Hashimoto T, et al. (2021) Diagnostic capability of cerebrospinal fluid-placental alkaline phosphatase value in intracranial germ cell tumor. Oncology 99:23\u0026ndash;31. https://doi.org/10.1159/000509395\u003c/li\u003e\n\u003cli\u003eOki S, Yamaguchi S, Okamoto M, Ishi Y, Kanno-Okada H, Takakuwa E, et al. (2025) Mature teratoma with a germinoma component presenting with undetectable placental alkaline phosphatase in cerebrospinal fluid: illustrative case. J Neurosurg Case Lessons 9:CASE24588. https://doi.org/10.3171/CASE24588\u003c/li\u003e\n\u003cli\u003eQaddoumi I, Sane M, Li S, Kocak M, Pai-Panandiker A, Harreld J, et al. (2012) Diagnostic utility and correlation of tumor markers in the serum and cerebrospinal fluid of children with intracranial germ cell tumors. Childs Nerv Syst 28:1017\u0026ndash;1024. https://doi.org/10.1007/s00381-012-1762-4\u003c/li\u003e\n\u003cli\u003eRotmensch S, Cole LA (2000) False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet 355:712\u0026ndash;715. https://doi.org/10.1016/S0140-6736(00)01324-6\u003c/li\u003e\n\u003cli\u003eSaleh U, Lim LH, Ismail I, Wahab NA (2021) Misdiagnosis of elevation of \u0026beta;-hCG in cystic craniopharyngioma: illustrative case. J Neurosurg Case Lessons 1:CASE2025. https://doi.org/10.3171/CASE2025\u003c/li\u003e\n\u003cli\u003eSch\u0026ouml;nberger S, Mohseni MM, Ellinger J, Tran GVQ, Becker M, Claviez A, et al. (2023) MicroRNA-profiling of miR-371~373- and miR-302/367-clusters in serum and cerebrospinal fluid identify patients with intracranial germ cell tumors. J Cancer Res Clin Oncol 149:791\u0026ndash;802. https://doi.org/10.1007/s00432-022-03915-4\u003c/li\u003e\n\u003cli\u003eTrap\u0026eacute; J, Fern\u0026aacute;ndez-Gal\u0026aacute;n E, Auge JM, Carbonell-Prat M, Filella X, Mir\u0026oacute;-Ca\u0026ntilde;\u0026iacute;s S, et al. (2024) Factors influencing blood tumor marker concentrations in the absence of neoplasia. Tumour Biol 46:S35\u0026ndash;S63. https://doi.org/10.3233/TUB-220023\u003c/li\u003e\n\u003cli\u003eYu Y, Lu X, Yao Y, Xie Y, Ren Y, Chen L, et al. (2023) A 2-step prediction model for diagnosis of germinomas in the pineal region. Neurooncol Adv 5:vdad094. https://doi.org/10.1093/noajnl/vdad094\u003c/li\u003e\n\u003cli\u003eZhang H, Zhang P, Fan J, Qiu B, Pan J, Zhang X, et al. (2016) Determining an optimal cutoff of serum \u0026beta;-human chorionic gonadotropin for assisting the diagnosis of intracranial germinomas. PLoS One 11:e0147023. https://doi.org/10.1371/journal.pone.0147023\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pineoblastoma, β-hCG, Pineal region tumour, Germinoma ","lastPublishedDoi":"10.21203/rs.3.rs-7261925/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7261925/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHuman chorionic gonadotropin (hCG) is a hormone that may be abnormally secreted in several tumour types, including intracranial germ cell tumours. In pineal region tumors, hCG is a key tumor marker. In fact, mild elevation typically suggests a germinoma with syncytiotrophoblastic cells, whereas a markedly elevated level indicates a choriocarcinoma or a mixed germ cell tumor with trophoblastic differentiation. While histopathological confirmation remains the diagnostic gold standard, the anatomical situation of the pineal gland makes biopsy very challenging. In certain situations, diagnosis may therefore rely on a constellation of clinical, radiological, and biochemical findings, including cerebrospinal fluid (CSF) β-hCG levels. However, the differential diagnosis of pineal region tumours includes other primary neoplasms of the pineal parenchyma, which differ markedly in both prognosis and therapeutic management. Here, we report two cases of pineoblastoma with unexpectedly elevated CSF β-hCG levels, which might have led to a misdiagnosis of intracranial germinoma. These cases highlight the need for the development of novel, non-invasive biomarkers to improve the diagnostic accuracy of intracranial tumours.\u003c/p\u003e","manuscriptTitle":"Elevation of hCG in CSF in pinealoblastoma: a pitfall rescued by pathological examination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 07:02:01","doi":"10.21203/rs.3.rs-7261925/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2025-10-07T14:54:33+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-29T15:10:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"306952023111332961329408285497643788683","date":"2025-09-12T18:30:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-18T17:49:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-08T13:00:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-08T12:58:32+00:00","index":"","fulltext":""},{"type":"submitted","content":"Acta Neuropathologica Communications","date":"2025-07-31T11:46:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"acta-neuropathologica-communications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"anec","sideBox":"Learn more about [Acta Neuropathologica Communications](https://actaneurocomms.biomedcentral.com/)","snPcode":"40478","submissionUrl":"https://submission.springernature.com/new-submission/40478/3","title":"Acta Neuropathologica Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d1197f4-eda3-4c91-81e2-9ed5e9d424d4","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:05:16+00:00","versionOfRecord":{"articleIdentity":"rs-7261925","link":"https://doi.org/10.1186/s40478-025-02148-z","journal":{"identity":"acta-neuropathologica-communications","isVorOnly":false,"title":"Acta Neuropathologica Communications"},"publishedOn":"2025-11-21 15:59:15","publishedOnDateReadable":"November 21st, 2025"},"versionCreatedAt":"2025-08-27 07:02:01","video":"","vorDoi":"10.1186/s40478-025-02148-z","vorDoiUrl":"https://doi.org/10.1186/s40478-025-02148-z","workflowStages":[]},"version":"v1","identity":"rs-7261925","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7261925","identity":"rs-7261925","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}