Intracranial Germinomas: Diagnosis, Pathogenesis, Clinical Presentation, and Management.

PURPOSE OF REVIEW: Intracranial germinomas constitute a rare brain tumor entity of unknown etiology, characterized by unique histopathology and molecular biology. In this manuscript, we review the literature focusing on the epidemiology, histopathology with molecular biology, clinical presentation with emphasis on tumor location, diagnostic workup, and current treatment strategies with related clinical outcomes of intracranial germinomas. RECENT FINDINGS: Although the optimal treatment strategy remains a matter of debate, intracranial germinomas respond well to radiotherapy, chemotherapy, or a combination of both and are characterized by very high cure and survival rates. It is well-known that early discrimination of germinomas from other intracranial neoplasms facilitates the timely initiation of appropriate treatment, thereby contributing to the reduction of morbidity as well as mortality. Ongoing research will need to be directed towards discovering and refining reliable parameters for early diagnosis and evaluation of prognosis in patients with intracranial germinomas.

Clinical significance and pitfalls of human chorionic gonadotropin-related tumor markers for intracranial germinomas.

PURPOSE: Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGß, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. METHODS: We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGß, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. RESULTS: The positivity rates of serum hCGß, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGß (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGß, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively. CONCLUSION: Serum intact and total hCGs have higher detection rates than hCGß in patients with germinoma using available commercial measurement tools.

Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

Epidemiology, Management, and Long-Term Survival Outcomes of Intracranial Typical Site Germinomas: An Analysis of the Surveillance, Epidemiology, and End-Results (SEER) Database.

BACKGROUND: The correlations of epidemiological characteristics and clinical outcomes with different tumor sites in patients with intracranial typical site germinomas (ICTSGs) have not yet been well established. We analyzed ICTSGs using a multicenter database, focusing on its demographic, management patterns, and long-term survival outcomes. METHODS: Patients diagnosed with ICTSGs were selected from the Surveillance, Epidemiology, and End-Results (SEER) database. Demographic information and management patterns of ICTSGs were extracted for data analysis stratified by different tumor sites. Kaplan-Meier curves were used to evaluate the survival outcome stratified by treatment, tumor site and tumor size. RESULTS: Among the 327 patients enrolled in the study, 16.21% had tumors located in the suprasellar region and 83.79% in the pineal region. The proportion of males was significantly higher among pineal germinomas (94.16 vs 66.04%; P < .001). Smaller tumors (<24 mm) were more common in the suprasellar region (37.74 vs 18.87%; P < .001). A higher percentage of patients with suprasellar germinomas underwent surgery. Radiotherapy (RT) and chemotherapy (CT) was, respectively, administered to 82.97 and 60.61% of patients during the treatment period, with no significant difference between suprasellar and pineal germinomas. CT plus RT was the most common treatment modality for both pituitary (30.19%) and pineal (33.94%) germinomas. Both RT and CT were associated with improved long-term survival. No survival difference was observed between suprasellar and pineal germinomas. CONCLUSIONS: Despite significant differences in epidemiology and management, pineal and suprasellar germinomas had a similar long-term clinical outcome.

Sellar germinoma mimicking IgG4-related hypophysitis: a case report.

BACKGROUND: The differential diagnosis of IgG4-related hypophysitis and other inflammatory diseases or tumors involving sellar region is challenging even after sellar biopsy. Sellar germinoma is usually infiltrated by lymphocytes or plasma cells, and may be confused with hypophysitis. CASE PRESENTATION: A 36-year-old man with diabetes insipidus, elevated serum IgG4 level (336 mg/dl), and sellar mass was suspected to have IgG4-related hypophysitis, and no other lesion of IgG4-related disease was detected. After treated by prednisone and mycophenolate mofetil, the serum IgG4 decreased to 214 mg/dl. However, after withdrawal of the drugs, the IgG4 level increased to 308 mg/dl. Endocrine assessments revealed panhypopituitarism, and the sellar mass enlarged. Transsphenoidal sellar exploration and biopsy was conducted. Pathological examination showed that the lesion was germinoma with lymphocytes and plasma cells infiltration, and IgG4-staining was positive (70/HPF, IgG4/IgG ratio = 10%). The patient was then treated by cisplatin and etoposide. After four cycles of chemotherapy, the serum IgG4 was 201 mg/dl, and the sellar mass was invisible. CONCLUSION: Sellar germinoma can mimic the clinical characteristics of IgG4-related hypophysitis. Poor response to glucocorticoids can be used as an exclusion criterion in the clinical diagnosis of IgG4-related hypophysitis.

Fast-developing fatal diffuse leptomeningeal dissemination of a pineal germinoma in a young child: a case report and literature review.

BACKGROUND: Intracranial germinomas are uncommon and constitute less than 1% of all intracranial tumors. They usually arise in the midline of the brain, most commonly in the pineal region. Pineal germinomas tend to spread through the cerebrospinal fluid (CSF). However, pineal germinomas with fast-developing diffuse subarachnoid/leptomeningeal dissemination are extremely rare, especially in young children. METHODS: The case of a 4-year-old boy with a pineal germinoma who died of diffuse subarachnoid/leptomeningeal dissemination 1 month after radiotherapy is reported. A PubMed search with specific key terms was used to review cases of pineal germinomas with metastasis. RESULTS: The patient presented with a two-week history of worsening headache, visual disturbances and nonprojectile vomiting. Parinaud's sign was positive on physical examination. Head computed tomography (CT)/magnetic resonance imaging (MRI) revealed a lesion in the pineal region with eccentric calcification and obvious supratentorial hydrocephalus. Pineal germinoma was suspected. A ventriculoperitoneal (VP) shunt followed by focal radiotherapy ameliorated the headaches and visual disturbances. The patient was discharged home without further treatment due to financial difficulties. One month after discharge, he was readmitted due to worsening headache, vomiting and lethargy. MRI showed a decrease in the size of the pineal lesion but revealed a diffuse leptomeningeal enhancement including the sulcus, basal cistern, prepontine cistern, and supravermian cistern. The patient's condition deteriorated rapidly, and he died 26 hours after readmission. The characteristics of pineal germinomas with metastasis are reported based on a review of the literature. CONCLUSIONS: Metastases in pineal germinomas predominately occur in adolescents or young adults, most commonly as spinal "drop metastases." Dissemination usually develops several years after the initial tumor diagnosis and has a relatively good clinical prognosis. However, fast widespread subarachnoid/leptomeningeal dissemination and sudden death may occur in a young child before salvage treatment, as in the presented case.

[Clinical analysis of 30 cases of basal ganglia germinoma in children].

OBJECTIVE: To summarize and analyze the clinical characteristics of children with basal ganglia germinoma and to improve the level of early clinical diagnosis. METHODS: The clinical data of children diagnosed with basal ganglia germinoma admitted to the Pediatric Surgery Ward of Peking University First Hospital from January 2013 to December 2020 were retrospectively analyzed, and descriptive statistics were used to analyze the clinical characteristics of children with basal ganglia germinoma. RESULTS: A total of 30 patients were included in the study, 28 were male, 2 were female, the mean age at onset was (9.7±2.2) years, the median disease duration was 7 months, 27 had unilateral disease, and 3 had bilateral disease. The clinical manifestations were decreased limb muscle strength, cognitive function disorders, polydipsia, precocious puberty, intracranial hypertension, dysphonia and swallowing dysfunction. The serum and cerebrospinal fluid tumor marker alpha-fetoprotein (AFP) were normal in the 30 patients, and the serum and cerebrospinal fluid tumor marker ß-human chorionic gonadotropin (ß-HCG) were normal in 8 patients.The serum ß-HCG was normal in 11 patients but the cerebrospinal fluid ß-HCG was slightly elevated, and the serum and cerebrospinal fluid ß-HCG were slightly elevated in 11 patients. A total of 33 lesions with irregular shapes were found by imaging examination, including 15 (45.5%) patchy lesions, 10 (30.3%) patchy lesions, and 8 (24.2%) round-like high-density lesions. Tumors showed obvious high-density shadows on computed tomography (CT) scan. Magnetic resonance imaging (MRI) scan of the tumors showed low or isointensity on T1WI and isointensity on T2WI, accompanied by mild peritumoral edema, hemispheric atrophy, cerebral peduncle atrophy, calcification, cystic degeneration, ventricular dilatation and wallerian degeneration. On contrast-enhanced scans, the tumor showed no enhancement or heterogeneous enhancement. CONCLUSION: The main age of onset of germ cell tumors in the basal ganglia in children is about 10 years old, and males are absolutely dominant. The clinical features and imaging manifestations have certain characteristics. With both combined, the early diagnosis of germ cell tumors in the basal ganglia can be improved.

[Evolving Exploration of the Pathogenesis of CNS Germ Cell Tumors with Regard to Precision Medicine].

Genomic and epigenomic analyses have progressed the exploration of the pathogenesis of CNS germ cell tumors(GCTs)in the past decade. GCTs are characterized by mutations in MAPK or PI3K pathways(55%)and unstable chromosomes, especially 12p gain(45%), as well as global hypomethylation in germinoma. Highly specific microRNA, miR-371a-3p, can be a diagnostic marker in serum and cerebrospinal fluid. Tumor cell content examined in H-E specimens has a prognostic value in germinoma: cases with higher tumor cell content show a worse prognosis. 12p gain in non-germinomatous GCTs(NGGCTs)has an unfavorable prognostic significance. PD-L1 and PD-1 are highly expressed in germinomas and the tumor cell microenvironment, respectively, highlighting the potential effectiveness of immune checkpoint inhibitors. Clinical trials from the Children's Oncology Group(COG)in the US and the Society for Paediatric Oncology(SIOP)in Europe and Japan have shown that whole ventricular irradiation is the most appropriate for germinomas, and that radiation fields can be reduced to the whole ventricle or a local area for localized NGGCTs. Toward personalized medicine, investigations into the structural abnormalities and variants in non-coding regions are needed to develop targeted therapy. A stratified treatment regimen is expected by incorporating newly-found biomarkers to reduce the treatment burden for generally young patients and circumvent late toxicity and sequelae. Establishing effective treatments is crucial for relapsed GCT that has a dismal prognosis.

[The value of CXorf67 and H3K27me3 for diagnosing germ cell tumors in central nervous system].

Objective: To investigate immunohistochemical patterns of CXorf67 and H3K27me3 proteins in central nervous system germ cell tumors (GCTs) and to assess their values in both diagnosis and differential diagnosis. Methods: A total of 370 cases of central nervous system GCTs were collected from 2013 to 2020 at Huashan Hospital of Fudan University, Shanghai, China. The expression of CXorf67, H3K27me3 and commonly-used GCT markers including OCT4, PLAP, CD117, D2-40, and CD30 by immunohistochemistry (EnVision method) was examined in different subtypes of central nervous system GCTs. The sensitivity and specificity of each marker were compared by contingency table and area under receiver operating characteristic (ROC) curve. Results: Of the 370 cases there were 282 males and 88 females with a mean age of 19 years and a median age of 17 years (range, 2-57 years). Among the GCTs with germinoma, the proportions of male patients and the patients with GCT located in sellar region were both higher than those of GCTs without germinoma (P<0.05), respectively. CXorf67 was present in the nuclei of germinoma and normal germ cells, but not in other subtypes of GCT. H3K27me3 was negative in germinoma, but positive in the nuclei of surrounding normal cells and GCTs other than germinoma. In the 283 GCTs with germinoma components, the expression rate of CXorf67 was 90.5% (256/283), but no cases were positive for H3K27me3. There was also an inverse correlation between them (r2=-0.831, P<0.01). The expression rates of PLAP, OCT4, CD117 and D2-40 were 81.2% (231/283), 89.4% (253/283), 73.9% (209/283) and 88.3% (250/283), respectively. In 63 mixed GCTs with germinoma components, the expression rate of CXorf67 was 84.1% (53/63), while all cases were negative for H3K27me3. The expression rates of PLAP, OCT4, CD117 and D2-40 were 79.4% (50/63), 79.4% (50/63), 66.7% (42/63) and 87.3% (55/63), respectively. The 6 markers with largest area under ROC curve in ranking order were H3K27me3, CXorf67, D2-40, OCT4, PLAP and CD117 (P<0.05). Conclusions: CXorf67 and H3K27me3 have high sensitivity and high specificity in diagnosing germinoma. There is a significant inverse correlation between them. Therefore, they can both be used as new specific immunohistochemical markers for the diagnosis of GCTs.

Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance.

AIMS: Alterations in microenvironments are a hallmark of cancer, and these alterations in germinomas are of particular significance. Germinoma, the most common subtype of central nervous system germ cell tumours, often exhibits massive immune cell infiltration intermingled with tumour cells. The role of these immune cells in germinoma, however, remains unknown. METHODS: We investigated the cellular constituents of immune microenvironments and their clinical impacts on prognosis in 100 germinoma cases. RESULTS: Patients with germinomas lower in tumour cell content (i.e. higher immune cell infiltration) had a significantly longer progression-free survival time than those with higher tumour cell contents (P = 0.03). Transcriptome analyses and RNA in-situ hybridization indicated that infiltrating immune cells comprised a wide variety of cell types, including lymphocytes and myelocyte-lineage cells. High expression of CD4 was significantly associated with good prognosis, whereas elevated nitric oxide synthase 2 was associated with poor prognosis. PD1 (PDCD1) was expressed by immune cells present in most germinomas (93.8%), and PD-L1 (CD274) expression was found in tumour cells in the majority of germinomas examined (73.5%). CONCLUSIONS: The collective data strongly suggest that infiltrating immune cells play an important role in predicting treatment response. Further investigation should lead to additional categorization of germinoma to safely reduce treatment intensity depending on tumour/immune cell balance and to develop possible future immunotherapies.

Intracranial Germinoma Masquerading as Secondary Granulomatous Hypophysitis: A Case Report and Review of Literature.

Germinomas are highly immunogenic tumors eliciting a strong peri-tumoral immune response that can spillover into the surrounding healthy tissues. This phenomenon can also occur in intracranial germinomas, manifesting as secondary hypophysitis. Herein, we report a case of 12-year-old-girl presenting with polyuria and polydispsia. She had central diabetes insipidus (CDI) and panhypopituitarism. Imaging revealed a sellar-suprasellar mass with infundibular stalk thickening. Transphenoidal biopsy revealed epithelioid granulomas with immunostaining negative for germinomatous cells. Other causes of hypophysitis were ruled out. Accordingly, she was diagnosed as primary granulomatous hypophysitis and treated with high-dose corticosteroids. Three years later she again presented with headache, vomiting and diminution of vision. Imaging showed a heterogeneous, solid-cystic peripheral rim-enhancing lesion at the same location with involvement of hypothalamus, ependyma and pineal gland. Cerebrospinal fluid beta-human chorionic gonadotropin was markedly elevated, confirming the diagnosis of an intracranial germ cell tumor. She was started on chemotherapy; however, she succumbed to febrile neutropenia. We performed a literature search and found 18 anecdotal cases of secondary hypophysitis associated with intracranial germinomas. There was a slight male preponderance (male:female 5:4). Two-thirds of the cases were below 18 years of age. Polyuria was the most common presenting manifestation (83%). CDI and panhypopituitarism were seen in 89 and 78% cases, respectively. Imaging evidence of pituitary stalk thickening was seen in 12 cases (67%), while pituitary enlargement and/or sellar mass were reported in 11 cases (61%). Pineal involvement was extremely rare, being reported in only 1 case, implying the predilection of suprasellar (rather than pineal) germinomas in causing secondary hypophysitis. Histologically, 82% had lymphocytic hypophysitis, while 18% had granulomatous hypophysitis. Initially, the diagnosis of germinoma was missed in 60% of the cases who were wrongly treated with corticosteroids. To conclude, physicians should make it a dictum that all children and adolescents presenting with CDI and pituitary stalk thickening should be rigorously screened for an underlying intracranial germinoma before labeling them as primary hypophysitis.

Cerebral Sinovenous Thrombosis and Subdural Hematoma as Treatment-Related Complications in Suprasellar Germ Cell Tumor Associated with Adipsic Diabetes Insipidus.

Cerebral sinovenous thrombosis (CSVT) is a rare but not a negligible complication in pediatric brain tumor. An 11-year-old male with suprasellar germ cell tumor developed treatment-related vascular complications of CSVT and subdural hematoma. The underlying mechanism of CSVT was attributed to multiple risk factors, such as adipsic diabetes insipidus, obesity, central apnea, and chemotherapy-induced endothelial injury. In an attempt to minimize the possible risk of vascular complications, including late effect in pediatric brain tumors, we would like to stress the importance of individualized supportive therapy, i.e., hormone replacement, fluid management, thromboprophylaxis, and bi-level positive airway pressure therapy.

Identification of characteristic features of pineal germinoma that enhance accuracy of preoperative differentiation in pineal region tumors: its significance on optimum surgical treatment.

The aim of the study is to identify characteristic features of pineal germinoma that enhance preoperative accuracy in differentiating germinoma from other pineal region tumors. Twenty-one consecutive patients with pineal region tumors were enrolled. In all patients, tumor resection was performed to verify the histology. Clinical records including upward gaze palsy of Parinaud's syndrome and neuroimaging were analyzed. In addition, we evaluated the relationship between magnetic resonance imaging (MRI) findings and tumor progression patterns in pineal germinoma. Among 21 patients, 15 patients were diagnosed with germ cell tumor, 4 with pineal parenchymal cell tumor, and 2 with meningioma. Upward gaze palsy was seen in 11 patients; nine had pure germinomas and two had mixed germ cell tumors. These tumors occupied the pineal region with extension to the area of the mesodiencephalic junction (MDJ) and the bi-epithalamic area between the bilateral pulvinar and the third ventricle. Tumor involvement of the former area could cause upward gaze palsy by insulting the rostral interstitial nucleus of the medial longitudinal fasciculus located in the MDJ area. Tumor invasion into the latter area is commonly seen as a cardioid-shaped tumor as the tumor image on the axial MRI view. Upward gaze palsy and a cardioid-shaped tumor image on the axial MRI views were demonstrated to be specific features of pineal pure germinoma. It is suggested that combination of both features may become useful tools to preoperatively differentiate germinoma from other pineal tumors, resulting in achievement of the optimum treatment of pineal region tumors.

Significance of human chorionic gonadotropin as a predictor of resistance to standard chemo-radiotherapy for pure germinoma.

Intracranial pure germinomas in children generally respond well to standard chemo-radiotherapy. However, some patients are refractory to standard therapy and require additional treatment. To investigate the characteristics of this subgroup, we retrospectively analyzed the clinical features and treatment outcomes of a cohort of 21 patients with intracranial pure germinomas who were diagnosed between April 2002 and December 2016 at Ehime University Hospital in Japan. Pure germinoma diagnosis was verified by histological examination of the tumor after surgery, and all patients received standard chemo-radiotherapy. A suite of clinical features, including neuroimaging, human chorionic gonadotropin-ß subunit (HCG-ß), and α-fetoprotein (AFP) in the cerebrospinal fluid (CSF), as well as immunohistochemical expression of HCG-ß, AFP, and Ki-67 in the tumor tissue were analyzed. Nineteen of the 21 patients had a complete response to standard chemo-radiotherapy without early recurrence of the tumors. Of these 19 patients, 17 did not have elevated CSF HCG-ß levels or express HCG-ß in the tumor tissue. However, the two patients who were refractory to standard therapy had elevated CSF HCG-ß levels and expressed HCG-ß in the tumor cells. These data suggest that patients with pure germinoma presenting with both an elevation of HCG-ß in the CSF and HCG-ß expression in the tumor tissue may be refractory to frontline treatment. These markers may predict aggressive germinoma and may ultimately facilitate the development of more effective treatment options.

Primary extramedullary spinal germinoma: case report and review of the literature.

The authors describe a case of a purely primary extramedullary spinal germinoma in a young Chinese male. Primary spinal germinoma is extremely rare tumor. Currently, less than 30 histologically verified spinal germinoma cases have been reported previously, mostly involving Asian of Japanese descent. This 24-year-old male suffered from progressive low back pain radiating to both legs. Magnetic resonance imaging showed a well-demarcated, intradural extramedullary mass at the level of L2 and L3. The lesion was totally removed and was confirmed as a germinoma. Upon histological verification of the tumor, he was treated successfully with radiotherapy and adjuvant chemotherapy. This report also reviews the literature pertaining to primary spinal germinoma. Except for 16 cases with intramedullary lesions and five cases with both intra- and extramedullary tumors, there were only three previously reported cases of extramedullary spinal germinomas, all initially presenting with sausage-like lesions. To the authors' knowledge, it is thought to be the first case of such a tumor, roughly round in shape and extramedullary location. Although rare, primary spinal germinoma do occur and should be included in the differential diagnosis of spinal tumors. Aggressive malignant behavior has been reported and close follow-up is necessary.

A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours.

BACKGROUND: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. METHODS: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. RESULTS: The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. CONCLUSIONS: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.

Radiographic occult cerebellar germinoma presenting with progressive ataxia and cranial nerve palsy.

BACKGROUND: Although the usefulness of susceptibility-weighted imaging (SWI) for detecting basal ganglia germinoma has been reported, the technique is not widely used. We recently encountered an unusual case of primary cerebellar germinoma, presenting with progressive ataxia and cranial nerve palsy, characterized by gradually enlarging low-intensity lesions visible with both T2*-weighted imaging (T2*WI), which were the key to the diagnosis. CASE PRESENTATION: A 30-year-old man was referred to our hospital because of slowly progressive dizziness and mild ataxia. Magnetic resonance imaging (MRI) revealed a small, low-intensity spot in the left cerebellar peduncle on the T2*WI and SWI without enhancement. Cerebral angiography revealed no vascular abnormality. The serum α-fetoprotein value was normal. A steroid-pulse was administered as a therapeutic and diagnostic trial, but the symptoms improved little. The patient was discharged from the hospital but soon developed brainstem dysfunction, characterized by dyspnea or hiccups, and he was readmitted. T2*WI imaging revealed expanded and extended spotty lesions in the cerebellum and brainstem, which had not enhanced with contrast agent previously. Targeted stereotactic biopsy of the newly enhanced cerebellar lesion was performed; histopathological examination of the tissue revealed pure germinoma. Serum and cerebral spinal fluid values of beta-human chorionic gonadotropin were not significantly elevated. Chemotherapy with carboplatin and etoposide was initiated. The enhanced lesion disappeared promptly, but the patient continued to require assisted automatic ventilation because of paralysis of respiratory muscles. CONCLUSIONS: We conclude that enlarging low-intensity lesions on T2*WI and SWI may be a reliable clue to the diagnosis of germinomas, irrespective of their location, even without enhancement. Biopsy of the tumor at an early stage is the only way to make the diagnosis conclusively and enable prompt start of treatment.