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

Background Intracranial germ cell tumors (GCTs), accounting for 2%–3% of pediatric brain tumors, are diagnostically challenging. GCTs are classified into germinomas and nongerminomatous germ-cell tumors (NGGCTs), which include yolk sac tumors, choriocarcinomas, and mixed tumors. Neuroimaging alone often cannot differentiate GCTs from other tumors, making biomarkers like a-fetoprotein (AFP) and human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) crucial for diagnosis. Elevated AFP indicates yolk sac tumors, while increased hCG suggests choriocarcinomas. Measuring these markers in CSF is more reliable than in serum and aids in monitoring treatment response and detecting recurrence. Matrix effects can impact test results when alternative sample types are used; therefore, validation is essential before clinical implementation. In this study, we validated AFP and hCG assays on the Abbott Alinity I platform. Methods To prepare the samples, clear and colorless CSF samples were initially tested to confirm the absence of alpha-fetoprotein (AFP) and human chorionic gonadotropin (hCG). Subsequently, serum samples with high concentrations of AFP and hCG were spiked into the CSF to create a range of concentrations. Linearity/Recovery Linearity was initially evaluated by testing singlet CSF samples with varying AFP and hCG concentrations across the serum AMR, which spans 0.1 to 2000 µg/L for AFP and 1.2 to 5000 IU/L for hCG, to determine the proposed linearity range. The linearity range was then confirmed by testing newly prepared samples within the proposed range in duplicate or triplicate. Precision Within-day imprecision was assessed by measuring two pools 10 times in a single day at target concentrations of 25, 500, and 1500 µg/L for AFP and 25, 1000, and 4000 IU/L for hCG. Day-to-day imprecision was evaluated by assaying individual aliquots four times daily over five days at the same target concentrations. Limit of quantitation LOQ was defined as the lowest concentration measured with a coefficient of variation (CV) <20% and total error <20%. Samples were assayed eight times per day over five days. Four CSF specimens containing AFP and hCG at concentrations ranging from 0.1 to 1.0 µg/L (0.1, 0.2, 0.5, 1.0) and 1.2 to 3 IU/L (1.2, 1.5, 2, 3), respectively, were analyzed to determine the LOQ. Sample Stability Sample stability was evaluated at 25°C (48 hours) and 4°C (12 days) to assess potential changes in analyte concentration over time. Stability was considered acceptable if the variation in concentration remained within 15% of the original test result. Carryover The carryover is assessed by comparing the response of a high-concentration sample (approximately 80% of the ULOQ) following a CSF blank. Results The method showed a linear range of 0.1–2000 µg/L for AFP and 2–5000 IU/L for hCG in CSF, with no significant matrix effect. Precision was <5% CV, and CSF samples remained stable for 48 hours at 25°C and 12 days at 2–8°C. LOQ was 0.1 µg/L for AFP and 2 IU/L for hCG, with no significant carryover. Conclusions: The Abbott Alinity I AFP and hCG assays accurately quantify AFP and hCG in CSF.

Our study objective was to validate 2 individual methods to measure α-fetoprotein (AFP) and human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) on the Roche cobas® 6000 analyzer. A 3-year retrospective chart review of CSF samples analyzed for AFP and hCG was also conducted. Serum samples with high concentrations of AFP or hCG were added to aliquots of pooled CSF. Precision, linearity, detection limit, recovery, carryover, stability, and interference studies of the AFP and hCG+β assays were performed. Within-day and day-to-day assay imprecision for AFP and hCG assays were <5% at all concentrations tested. The linear range of the AFP assay was established as 1.0-1100 μg/L, and limit of quantification (LOQ) was <1.0 μg/L. The linear range of the hCG assay was established as 1.0-9500 IU/L and LOQ 0.7 IU/L. There was no demonstrable matrix effect, and neither assay was affected by the presence of hemolysis or xanthochromia. AFP in CSF was stable at room and refrigerated temperatures for up to 48 h at concentrations of 19 and 306 μg/L but increased by 24 h at a concentration of 908 μg/L. AFP in CSF was stable frozen (-20 °C) for up to 7 days. hCG in CSF at all concentrations tested was stable at room, refrigerated, and frozen temperatures for up to 7 days. The Roche cobas 6000 AFP and hCG+β assays accurately quantify AFP and hCG in CSF, facilitating rapid and accurate diagnosis as well as monitoring of intracranial germ cell tumors.

Rapidly Progressive Precocious Puberty With an Elevated Testosterone Level in a 5-Year-Old Boy With a β-Human Chorionic Gonadotropin-Secreting Intracranial Germ Cell Tumor in the Pineal Gland

Simple SummaryPineal region tumors are rare intracranial tumors. A deeper knowledge of these tumors’ molecular mechanisms has been gained in recent years, which has led to a new classification and new potential systemic treatments. Surgery remains the mainstay of treatment, while radiotherapy and systemic therapy depend on histological, molecular, and clinical characteristics. This paper highlights recent developments in the diagnosis and treatment of these tumors.Pineal region tumors are rare intracranial tumors, accounting for less than 1% of all adult intracranial tumor lesions. These lesions represent a histologically heterogeneous group of tumors. Among these tumors, pineal parenchymal tumors and germ cell tumors (GCT) represent the most frequent types of lesions. According to the new WHO 2021 classification, pineal parenchymal tumors include five distinct histotypes: pineocytoma (PC), pineal parenchymal tumors of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), pinealoblastoma (PB), and desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant; GCTs include germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma, mixed GCTs. Neuroradiological assessment has a pivotal role in the diagnostic work-up, surgical planning, and follow-up of patients with pineal masses. Surgery can represent the mainstay of treatment, ranging from biopsy to gross total resection, yet pineal region tumors associated with obstructive hydrocephalus may be surgically managed via ventricular internal shunt or endoscopic third ventriculostomy. Radiotherapy remains an essential component of the multidisciplinary treatment approach for most pineal region tumors; however, treatment volumes depend on the histological subtypes, grading, extent of disease, and the combination with chemotherapy. For localized germinoma, the current standard of care is chemotherapy followed by reduced-dose whole ventricular irradiation plus a boost to the primary tumor. For pinealoblastoma patients, postoperative radiation has been associated with higher overall survival. For the other pineal tumors, the role of radiotherapy remains poorly studied and it is usually reserved for aggressive (grade 3) or recurrent tumors. The use of systemic treatments mainly depends on histology and prognostic factors such as residual disease and metastases. For pinealoblastoma patients, chemotherapy protocols are based on various alkylating or platinum-based agents, vincristine, etoposide, cyclophosphamide and are used in association with radiotherapy. About GCTs, their chemosensitivity is well known and is based on cisplatin or carboplatin and may include etoposide, cyclophosphamide, or ifosfamide prior to irradiation. Similar regimens containing platinum derivatives are also used for non-germinomatous GCTs with very encouraging results. However, due to a greater understanding of the biology of the disease’s various molecular subtypes, new agents based on targeted therapy are expected in the future. On behalf of the EURACAN domain 10 group, we reviewed the most important and recent developments in histopathological characteristics, neuro-radiological assessments, and treatments for pineal region tumors.

The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is useful for the differential diagnosis of suprasellar lesions. However, the concentrations that prove diagnostic for neurohypophyseal germinoma have not been well defined. In addition, the immunoassays used for such measurements are the same as those applied in serum, and few studies have been performed regarding the validation of such techniques in CSF. The present study aims to apply the Elecsys(®) hCG + β immunoassay from Roche Diagnostics to measure hCG in CSF, as a useful tool in the diagnosis of neurohypophyseal germinomas in children and young adults. Validation of the immunoassay involved calculation of the functional sensitivity and reference values for hCG in CSF in 35 controls in the absence of pregnancy, trophoblastic disease or tumour pathology. For the clinical application study, three patients diagnosed with neurohypophyseal germinoma have been reviewed. The functional sensitivity obtained was 0.4 IU/L. The reference values for hCG in CSF ranged from undetectable values to 0.7 IU/L. The hCG concentrations in CSF in the three studied patients, with confirmed diagnosis of neurohypophyseal germinoma, were 21.1, 32.6 and 23 IU/L, respectively. The Elecsys® hCG + β immunoassay from Roche Diagnostics can be used to detect hCG in CSF with high precision. According to our results, CSF-hCG concentrations that exceed the established reference interval (undetectable values to 0.7 IU/L) in the presence of suprasellar lesions and hypophyseal stalk thickening must be considered pathological, establishing the need to exclude the presence of germinoma.

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

Background. The measurement of human chorionic gonadotropin (hCG) in cerebrospinal fluid (CSF) is important for the diagnosis of intracranial or intraspinal trophoblastic tumours. The current study was performed to establish reference values for hCG in CSF and to explore the relationship of CSF hCG and serum hCG in patients who are not pregnant or do not have trophoblastic tumours. Material and methods. CSF samples were obtained from 369 inpatients admitted because of various neurological diseases, excluding pregnancy, trophoblastic tumours and other malignant tumours. In 271 of the 369 patients, paired samples of CSF and serum were obtained. Both CSF hCG and serum hCG were measured. The 97.5th percentile and maximum value of CSF hCG were obtained. The CSF hCG and serum hCG concentrations in each of the 271 paired samples were compared. Results. The 97.5th percentile and maximum value of CSF hCG concentration for overall participants were 1.00 and 5.00 IU/L, respectively. The CSF hCG concentration was found to be higher than the simultaneous serum hCG concentration in 81.9% (222/271) of the participants. Conclusions. The reference value determined in this study of CSF hCG in men is significantly lower than that usually used in clinical practice. A CSF hCG concentration higher than the simultaneous serum hCG concentration but lower than the upper reference limit does not necessarily suggest abnormal intrathecal hCG-secretion.

A 10-year-old, overweight girl presents to the clinic with 3 weeks of fever. She was in her usual state of health until 21 days before presentation, when she developed a fever in the setting of cough, congestion, abdominal pain, and myalgias. Her symptoms subsided within 5 days of onset, but she continued to have waxing and waning fevers, ranging between 102°F and 104°F (38.9°C–40.0°C), lasting for several days at a time, with occasional defervescence for up to 48 hours. She was seen in the pediatric clinic on day 7, where she was afebrile with normal examination findings. Respiratory viral polymerase chain reaction panel revealed a positive reaction to rhinovirus/enterovirus. She was diagnosed as having a viral illness and sent home with supportive care instructions regarding pyrexia management, optimizing hydration status, expected clinical course, and primary care follow-up as needed. For the next 2 weeks she had daily fevers and was seen in the emergency department several times, with documented examination findings suggesting no focal abnormalities and serial laboratory evaluations showing increasing values of inflammatory markers (white blood cell count, from 10,200/µL [10.2 × 109/L] to 15,300/µL [15.3 × 109/L]; C-reactive protein level, from 14 mg/dL [140 mg/L] to 21 mg/dL [210 mg/L]; and erythrocyte sedimentation rate, from 35 mm/hr to 51 mm/hr), with negative serial blood and urine cultures. She was seen again in the clinic during week 3 of illness with review of systems at that time noting 3 days of nausea as well as mild, intermittent abdominal bloating and discomfort. Vital signs at this visit show tachycardia (heart rate, 127 beats/min) and tachypnea (respiratory rate, 36 breaths/min), with normal pulse oximetry (99%) and blood pressure (105/68 mm Hg). Weight and height are both greater than the 99th percentile (Fig 1). Examination reveals an ill- and anxious-appearing young lady. She demonstrates rapid but nonlabored breathing and has a slightly distended, nontender abdomen without peritoneal signs, palpable mass, or hepatosplenomegaly. Her abdominal examination was functionally challenging due to baseline developmental delays, resulting in difficulty achieving a relaxed complete examination. A genitourinary examination was declined by the family.Her medical history is significant for idiopathic tall stature; chronic, presumed functional constipation; and a diagnosis of level 1 autism made at age 3 years with normal genetic testing. She is verbal with friends and family with an age-appropriate IQ but primarily communicates to providers through her parents. Historically, compliance with examinations has been limited due to communication delays. Nine months earlier her developmental pediatrician commented that she “appears much older than her stated age” and referred her to women’s health due to recent onset of menarche, which occurred shortly after her 10th birthday. Her periods at that time were listed as infrequent and irregular, lasting for 3 to 4 days on average and occurring every 4 to 8 weeks, with an estimated 2 and 3 pads per day needed to control flow on her heaviest days. Her parents reported that thelarche occurred between 6 and 7 years of age, with adrenarche concurrently appearing around this same time. A diagnostic evaluation for precocious puberty, including bone age, had not yet been pursued.The differential diagnosis at the time of her current evaluation in the clinic included infectious, connective tissue, and malignant pathologies. Specifically, there were concerns for secondary bacteremia after initial viral insult, an occult localized bacterial infection (urinary tract infection, intra-abdominal or pelvic abscess, pneumonia), a less typical bacterial process (mycobacterial, salmonellosis, toxoplasmosis) although no overt suggestive exposures were identified, or a protracted viral illness (cytomegalovirus, Epstein-Barr virus, adenovirus, enteroviruses). Primary vasculitis (immunoglobulin A vasculitis, polyarteritis nodosa), early manifestations of systemic lupus erythematosus, and inflammatory bowel disease were also considered. The presence of presumed precocious puberty and abdominal swelling increased concern for a hormonally active neoplastic process such as a gonadal tumor, adrenocortical carcinoma, or hepatoblastoma.Repeated inflammatory markers at this time were significantly elevated (white blood cell count, 23,800/µL [23.8 × 109/L]; C-reactive protein level, 302.1 mg/dL [3,021 mg/L]; erythrocyte sedimentation rate, 54 mm/hr). Radiographs of her chest and abdomen revealed a gasless abdomen and lingular atelectasis with a left-sided pleural effusion. A computed tomographic (CT) scan of the abdomen and pelvis showed ascites and a large, left-sided, complex pelvic mass that appeared adnexal in origin. Her serum α-fetoprotein (AFP) level was markedly elevated at 4,710 ng/mL (4,710 µg/L) (reference range, <8 ng/mL [<8 µg/L]), and her cancer antigen 125 (CA-125) level was high at 951 U/mL (951 kU/L) (reference range, <35 U/mL [<35 kU/L]). Based on these elevated tumor markers, presence of systemic symptoms, and abnormal chest radiographs, a CT scan of the chest was obtained and showed masses in the mediastinum with large, bilateral pleural effusions. She was diagnosed as having suspected metastatic primary ovarian malignancy. Surgical resection of her ovarian mass revealed a 30-cm, 4.59-kg mixed germ cell tumor consisting of 90% immature teratoma and 10% yolk sac tumor (Fig 2).Ovarian and other adnexal tumors are rare in the pediatric population, with an estimated incidence of 2.6 cases per 100,000 girls per year. (1) Most of these masses are benign, with approximately 10% demonstrating malignant potential. (2) In contrast to the adult population, the age-adjusted incidence of ovarian malignancy is 0.1 per 100,000 per year in girls and adolescent females compared with 11.4 per 100,000 per year in women older than 20 years. (3) Despite their infrequency, ovarian tumors are among the most common neoplasms of the genital tract in childhood and account for approximately 1% of all malignancies in females younger than 17 years. (4) These tumors thus represent an important component of pediatric oncology and often present a diagnostic dilemma for the general pediatrician because their clinical manifestations are nonspecific and often subtle.The most common presenting symptom of ovarian cancer is abdominal pain (57%), followed by a palpable abdominal or pelvic mass (46%). A small case series showed fever present in only 12% of patients, with nausea, vomiting, poor appetite, weight loss, constipation, precocious puberty, and urinary symptoms also occasionally noted on presentation. (5) Approximately 18% of cases are asymptomatic, with tumor being detected incidentally on routine physical examination or during diagnostic imaging for another purpose. There is tremendous overlap regarding the clinical manifestations of the various ovarian tumors, and distinguishing between tumor types often requires histopathologic determination. However, there are a few key features that can help distinguish benign from malignant neoplasms and may help direct the diagnostic evaluation and surgical approach. Children with a palpable mass or precocious puberty have a reportedly higher likelihood of malignancy. (6) Systemic inflammatory response syndrome, and pyrexia in particular (as described in this case), is an uncommon feature of ovarian tumors and, if present, suggests malignancy with metastatic spread. Ovarian torsion, although more commonly associated with no underlying pathologic lesion, seems to be a more frequent symptom of benign rather than malignant tumors. (7) Although not specific to ovarian malignancy, delays and errors in cancer diagnosis have been linked to cancers for which there is an atypical or nonspecific presentation, for which there is a very low prevalence of disease burden in the general population, and in children with comorbidities that may mask, alter, or add to the complexity of the presentation and examination. (8)Primary pediatric ovarian tumors generally fall into 1 of 3 categories based on their cell origins: germ cell tumors, epithelial-stromal tumors, and sex cord–stromal tumors (Table 1).Unlike in the adult population, where epithelial-stromal tumors predominate, germ cell tumors are by far the most common ovarian neoplasm discovered in children, accounting for 60% to 80% of cases. Although germ cell tumors are predominantly benign in adults, up to one-third of ovarian germ cell tumors are malignant in children. (9) In the category of germ cell tumors, 3 histologic subtypes predominate: teratomas, dysgerminomas, and yolk sac tumors. Teratomas include both immature (malignant) and mature (benign, predominantly cystic) forms. Dysgerminomas occur almost exclusively in patients with gonadal dysgenesis and thus have a proclivity for chromosomal conditions where this is a feature (eg, Turner syndrome). Yolk sac tumors, also known as endodermal sinus tumors, are rare and tend to be the most aggressive, malignant, and rapidly growing of the germ cell tumors. These tumors often present with extensive abdominopelvic cavity spread. Sex cord–stromal tumors arise from granulosa, theca, Leydig, or Sertoli cells and are unique in their proclivity to be hormonally active. Specifically, tumors with granulosa or theca cells typically produce estrogen, resulting in isosexual precocity. Sertoli-Leydig cell tumors have a tendency to produce androgen analogues, resulting in phenotypic androgen excess. Epithelial-stromal tumors are extremely uncommon before menarche because hormonal stimulation is typically required to activate their growth. (13)The stages of diagnostic evaluation depend on the clinical features evident at the onset of evaluation. Well-appearing females with a palpable abdominal mass suspected to be adnexal in origin should undergo imaging to determine whether the finding is more likely physiologic (eg, simple ovarian cyst) or neoplastic. Transabdominal ultrasonography is the imaging modality of choice in this case. If features concerning for malignancy are present, CT or magnetic resonance imaging should be pursued to elucidate the nature and extent of the tumor. Although it is difficult to distinguish between benign and malignant ovarian tumors purely from imaging, findings that suggest malignancy can be found in Table 2. (11)Once an ovarian tumor is discovered, assay of targeted tumor markers is the recommended next step to help facilitate diagnosis, dictate preoperative planning, and follow postoperatively for response to therapy. The most commonly cited serologic markers are serum AFP, β-human chorionic gonadotropin (β-hCG), CA-125, and inhibin. Serum AFP levels are primarily elevated in patients with malignant germ cell tumors, including yolk sac tumors, immature teratomas, and embryonal carcinomas. Although it is uncommon, AFP level can also be elevated in sex cord–stromal tumors. β-hCG levels are primarily linked to embryonal carcinomas and mixed germ cell tumors. CA-125 levels are commonly more elevated in patients with epithelial ovarian tumors than with germ cell tumors. This tumor marker, however, has low sensitivity and specificity for detection of ovarian malignancy in the pediatric population and can be elevated for a variety of benign reasons in postpubertal patients (endometriosis, ovarian torsion, menses). It thus has limited clinical utility in evaluation of pediatric ovarian tumors. Lactate dehydrogenase level is commonly elevated in dysgerminomas, and inhibin is a sensitive marker of tumor activity in sex cord–stromal tumors. Although tumor markers can be helpful, it is important to note that up to 46% of malignant tumors have no detectable elevations in tumor markers. (13) The ultimate nature of the tumor, malignant or benign, cannot be confirmed until histologic analysis is performed. Absence of metastases also does not exclude malignant histology.Contemporary management of ovarian germ cell tumors is evolving as collaboration among pediatric, genitourinary, and gynecologic oncologists continues to better characterize effective risk classifications, adjuvant therapy candidates, and surveillance strategies. (14) Surgical resection is the primary therapeutic modality for ovarian germ cell tumors, with oophorectomy or salpingo-oophorectomy serving as the definitive treatment for most cases. Adjuvant chemotherapy is considered for patients based on tumor stage, histologic findings, and risk stratification at the time of diagnosis but is typically reserved for children with metastasis beyond the ovary, residual disease, or failure of serum markers to normalize after resection (Table 3). (14) Candidates for postoperative chemotherapy are recommended to receive a platinum-based regimen, traditionally consisting of bleomycin, etoposide, and cisplatin. (14) A fertility-sparing surgical approach is considered the standard of care in pediatric patients with ovarian germ cell tumors, although surgical planning must take into account the unique clinical manifestations, presence of serum tumor markers, distinctive imaging features, and population-based tumor characteristics to generate an optimal approach. (12) Although cryopreservation of the nonaffected ovary may be considered, patients undergoing fertility-sparing unilateral salpingo-oophorectomy, even those requiring postoperative chemotherapy, have favorable fertility outcomes. Case series have shown that regular menstrual cycles return in 87% to 97% of women who had complete response to treatment (consisting of fertility-sparing surgery and platinum-based chemotherapy). (17)(18) Of those attempting conception after treatment, 75% were able to successfully achieve pregnancy. (18) Prognosis, including event-free and overall survival rates, depend primarily on age (<11 years old is considered a positive prognostic indicator), histopathologic tumor type, as well as the tumor stage at diagnosis but are generally favorable (Table 4). (19)(20) Of note, in children with hormonally active tumors resulting in precocious puberty, pediatric endocrinology plays a critical role in the initial evaluation and postoperative surveillance. Treatment of the primary malignancy with fertility-sparing techniques resolves or diminishes pubertal findings in almost all surviving patients with an intact hypothalamic-pituitary-gonadal axis. (21)The patient was diagnosed as having a rapidly growing mixed germ cell tumor with metastatic spread to the omentum and spread beyond the abdomen to the mediastinal lymph nodes (Children's Oncology Group stage IV). After salpingo-oophorectomy and greater oomenectomy she was started on chemotherapy with bleomycin, etoposide, and cisplatin. Her pleural effusions resolved shortly after tumor resection, and cytologic analysis showed transudative fluid with absent tumor burden. At the time of this writing, the patient tolerated her first round of chemotherapy well, with excellent response to interventions. Her most recent AFP levels were within normal limits.

Surgical Options for Pineal Region Tumors

Dear editor, For many years, in case of suspicion of a germ cell tumor (GCT), human chorionic gonadotropin (HCG), its beta subunit and alpha-fetoprotein (AFP) have been used as specific markers in the blood and/or cerebrospinal fluid (CSF) for clinical decision-making [4]. A positive test is an indication for treatment, without requiring histological confirmation [5]. We report a first description of CSF HCG elevation in a non-cystic suprasellar craniopharyngioma, contradicting this dogma. A 52-year-old male with a history of arterial hypertension and tinnitus complained of a decrease in left-side visual acuity over a few weeks, associated with polyuro-polydipsia syndrome. MRI examination revealed a suprasellar lesion of 16×18×16 mm, with a moderate hyper-T2 signal and an iso-T1 signal with homogeneous gadolinium enhancement. The lesion did not have a cystic component (see Fig. 1). Spinal MRI was negative, and the cerebral CT scan did not show any calcification of the tumor. Hormone analysis revealed a pituitary deficiency. Biological analysis of the CSF performed as part of the etiological assessment revealed an elevation of HCG to 10.8 IU/l (normal levels <5 IU/l) and of free beta-HCG to 1.1 ng/ml (normal levels <0.1 IU/l). Elevation of AFP was not detected in the blood or CSF. No abnormal cells were found in the CSF. No elevation of these markers was found in the blood. Given the many atypical features in our patient, we decided to perform a robot-assisted stereotaxic biopsy. The final diagnosis was papillary craniopharyngioma and excluded germinoma. Due to the high risk of surgical treatment, and after a multidisciplinary discussion, the tumor was treated by radiotherapy. Six months after that, the patient recovered his visual field loss, but the hypopituitarism remained. The MRI showed a volumetric reduction of the tumor and a decrease in contrast enhancement. This report points out two issues: First, some authors [2, 3, 6] have suggested that many cystic pineal, sellar or suprasellar lesions, including cystic craniopharyngioma, are able to produce theses markers through their wall (descriptions of HCG in benign pineal cyst contents and walls). This observation of a solid craniopharyngioma demonstrates for the first time that the tumor itself is able to secrete low levels of HCG and β-HCG that may be detectable in the CSF. CSF AFP elevation was also detected in two cases of craniopharyngiomas, one of which was proven to be a malignant form [2]. So far, no blood elevation of these markers has been reported in craniopharyngiomas. Second, therefore, physicians involved in brain management need to be aware that HCG or AFP CSF positivity in a patient with a suprasellar tumor is not a specific GCT signature and is not enough information for making therapeutic decisions. Our clinical case underlines the importance of multidisciplinary discussions and the necessity to perform a biopsy in patients showing isolated suprasellar lesions (bipolar pineal and suprasellar locations remain suggestive of germinoma), positive for CSF markers but with atypical P. Bourdillon (*) : E. Jouanneau Department of neurosurgery A, Hopital Neurologique et Neurochirurgical Pierre Wertheimer, Hospices Civils de Lyon, 59 bd Pinel, 69500 Bron, France e-mail: pierre.bourdillon@neurochirurgie.fr

Objective To conduct the comparative observational study of serum neoplastic biomarker and immunohistochemistry in intracranial germ cell tumors (GCTs). Methods A retrospective study was conducted on clinical data of 28 cases of germ cell tumors undergoing surgery from March 2013 to July 2016 at Tsinghua University Yuquan Hospital. Presurgical serum neoplastic biomarkers including α-fetoprotein (AFP), β-human chorionic gonadotropin (β-HCG) and alkaline phosphatase (ALP) were measured and compared with postsurgical immunohistochemistry results of tumor specimens. Results Among the 28 cases of GCTs, germinoma was identified in 5 cases, teratoma in 2 cases, immature teratoma in 5 cases, choriocarcinoma in 1 case and mixed germ cell tumor in 15 cases. AFP was inconsisent in 8/28 cases, being positive in serum biomarker and negative in immunohistochemistry, and included 4 cases of immature teratoma and 4 mixed GCTs. β-HCG was incongruent in 5 cases (positive in serum and negative in immunohistochemistry). Among the 18 cases with pure germinoma component, placenta ALP (PLAP) immunohistochemistry revealed positive results in 15 cases, while serum ALP was significantly increased in only 4 cases and not detected in the remaining 14 cases. Conclusions The treatment and prognosis of intracranial GCTs might be correlated with different neoplastic components. Immunohistochemistry combined with serum biomarker could help demonstrate those neoplastic components more accurately and completely. Key words: Central nervous system; Neoplasms, germ cell and embryonal; Neoplastic biomarker; Immunohistochemistry

In males, precocious puberty (PP) is defined as the development of secondary sexual characteristics before age 9 years. PP is usually idiopathic; though, organic abnormalities including tumors are more frequently found in male patients with PP. However, advanced puberty in male also can be an important clinical manifestation in tumors. We report 2 cases of rapidly progressive puberty in males, each associated with a germ-cell tumor. First, an 11-year-old boy presented with mild fever and weight loss for 1 month. Physical examination revealed a pubertal stage of G3P3 with 10-mL testes. Investigations revealed advanced bone age (16 years) with elevated basal luteinizing hormone and testosterone levels. An anterior mediastinal tumor was identified by chest radiography and computed tomography, and elevated α-fetoprotein (AFP) and β-human chorionic gonadotropin (β-hCG) levels were noted. Histopathologic analysis confirmed a yolk-sac tumor. Second, a 12-year-old boy presented with diplopia, polydipsia, and polyuria for 4 months. Physical examination revealed a pubertal stage of G3P3 with 8-mL testes. Bone age was advanced (16 years) and laboratory tests indicated panhypopituitarism with elevated testosterone level. A mixed germ-cell tumor was diagnosed with elevated AFP and β-hCG levels. Of course, these patients also have other symptoms of suspecting tumors, however, rapidly progressive puberty can be the more earlier screening sign of tumors. Therefore, in male patients with accelerated or advanced puberty, malignancy should be considered, with evaluation of tumor markers. In addition, advanced puberty in male should be recognized more widely as a unique sign of neoplasm.

In previous studies, patients with intracranial germ cell tumour (iGCT) with pure choriocarcinoma or mixed germ cell tumours with choriocarcinoma element showed similar dismal prognoses, with median overall survival (OS) of 22months and 1-year survival rate of approximately 60%. However, these conclusions need to be updated because radiotherapy, which is the mainstay for this disease, was not applied in a number of patients. Additionally, prognostic factors need to be explored in this population. Clinical data of patients with iGCTs with histologically confirmed choriocarcinoma element or beta-human chorionic gonadotropin (β-HCG) > 500IU/L were collected from the archives of our institution and retrospectively studied. A total of 76 patients were eligible for this study. Except for two early deaths, all patients received radiotherapy (craniospinal irradiation [CSI], n = 23; non-CSI, n = 51). The median follow-up duration for the entire series was 63months (range, 6-188months). The 5-year event-free survival (EFS) and OS rates were 81.5% and 84.1%, respectively. Among patients who did not have early death or progressive disease after induction chemotherapy, multivariate analysis revealed that chemotherapy cycles (> 4 vs. ≤ 4) (hazard ratio [HR] for EFS 0.144, p = 0.020; HR for OS 0.111, p = 0.028) and β-HCG levels (> 3000IU/L vs. ≤ 3000IU/L) (HR for EFS 4.342, p = 0.059; HR for OS 6.614, p = 0.033) were independent factors for survival. Patients with iGCTs with choriocarcinoma element or β-HCG > 500IU/L showed improved survival with radiotherapy-based treatments. Additional chemotherapy cycles could result in additional survival benefits. Patients with β-HCG level > 3000IU/L had poorer prognosis.

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.

We read with great interest the article entitled “Are stereotactic sample biopsies still of value in the modern management of pineal region tumours? Lessons from a single-department, retrospective series” by Lefranc et al. [2]. The authors retrospectively analyzed a series of 88 consecutive patients who underwent stereotactic biopsies for pineal region tumors. They reported that accurate tissue diagnoses were obtained in all but one case, and that the pathological diagnoses included 21 germ cell tumors as well as 32 pineal parenchymal tumors, 15 glial tumors, and 20 other tumors. They concluded that stereotactic biopsies for pineal region tumors could provide accurate pathological diagnoses with safety. We wish to provide further comments, especially regarding the issue of accurately diagnosing germ cell tumors. The authors performed staged biopsies to obtain as much tissue as possible and to optimize the sample collection. Furthermore, when the tumor was too small, they performed rosette biopsies by rotating the side-cut needle. The limited amount of tissue sampling in stereotactic biopsies could result in failure to make an accurate diagnosis, especially when dealing with tumors with mixed components, as mentioned by Lefranc et al. We agree with the authors’ device for avoiding sampling errors. On the other hand, we consider that it is necessary to provide additional information on whether mixed germ cell tumors can be accurately diagnosed in the authors’ series, since the authors did not mention these tumors. Matsutani et al. [3] reported that 32% of intracranial germ cell tumors had coexistence of more than two germ cell tumor components. Depending on the kinds of components present, the treatment strategies can vary, and the outcomes can differ significantly [1, 3]. If mixed germ cell tumors were not diagnosed, we consider that it is too early to reach conclusions on the accuracy of pathological diagnosis with stereotactic biopsies.