Novel Diagnostic Methods and Posttreatment Clinical Phenotypes Among Intracranial Germ Cell Tumors

Neurosurgery ◽  
2020 ◽  
Vol 87 (3) ◽  
pp. 563-572 ◽  
Author(s):  
Hirokazu Takami ◽  
Avital Perry ◽  
Christopher S Graffeo ◽  
Caterina Giannini ◽  
David J Daniels
Keyword(s):  
Cohort Study ◽  
Germ Cell ◽  
Statistical Significance ◽  
Mature Teratoma ◽  
Germ Cell Tumors ◽  
Extent Of Resection ◽  
Diagnostic Methods ◽  
Cell Fraction ◽  
Clinical Phenotypes ◽  
Second Look

Abstract BACKGROUND Central nervous system (CNS) germ cell tumors (GCT) are rare and complex pediatric neoplasms, the optimal management of which remains an area of active investigation. OBJECTIVE To present an updated cohort study, with particular attention to novel diagnostic methods and posttreatment clinical phenotypes. METHODS A single-institution cohort study of 80 primary, neurosurgically managed, CNS GCTs was conducted at Mayo Clinic, 1988-2017. RESULTS Postchemotherapy resection (eg, second-look surgery) was frequently required (27.0%), especially after adjuvant therapies for nongerminomatous GCTs (NGGCTs; 14 of 28 cases, excluding mature teratoma) and significantly associated with pineal lesions, as compared to neurohypophyseal or bifocal lesions (43.6% vs 5.9% vs 6.7%, P = .004), a finding that retained statistical significance after adjusting for index extent of resection and histology (P = .04). Essentially every NGGCT case underwent at least 1 craniotomy, either on presentation, as second-look surgery, or following local recurrence. Mature teratomatous tissue was highly incident in second-look specimens (84.2%), even among lesions initially diagnosed as germinomas. Pretreatment cerebrospinal fluid (CSF) cell fraction analysis demonstrated an association between single lesions and neutrophil predominance, whereas nongerminomatous GCTs were associated with increased monocyte fractions. CONCLUSION CNS GCTs are clinically heterogeneous lesions, resulting in numerous opportunities for improved understanding and clinical management via novel diagnostic and therapeutic protocols. Samples from second-look surgeries for recurrent germinomas frequently demonstrate teratomatous tissue, suggesting possible underdiagnosis of mixed GCTs—particularly among pineal lesions. GCT subtypes demonstrate differential cell fraction distributions on CSF analysis, a novel and perhaps diagnostically helpful finding that requires validation in external cohorts.

Prediction of residual retroperitoneal mass histology following postchemotherapy retroperitoneal surgery for metastatic nonseminomatous germ cell tumors: Role of MDR-1 and mismatch repair genes

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5088-5088
Author(s):  
A. N. Heidenreich ◽  
D. Pfister ◽  
D. Thüer ◽  
U. H. Engelmann ◽  
C. H. Ohlmann
Keyword(s):  
Multivariate Analysis ◽  
Germ Cell ◽  
Statistical Significance ◽  
Mature Teratoma ◽  
Tumor Resection ◽  
Germ Cell Tumors ◽  
Staining Intensity ◽  
Predictive Values ◽  
Preoperative Serum ◽  
Mdr 1

5088 Background: Following inductive chemotherapy for metastatic nonseminomatous germ cell tumours (NSGCT) about 35% and 15% of patients undergoing residual tumor resection (RTR) demonstrate mature teratoma and vital cancer, respectively. It was the aim of our study to evaluate the expression of mdr-1, hMLH1 and hMLH2 in primary NSGCT and their resected residual tumors. Methods: 185 patients with NSGCT underwent RTR of retroperitoneal masses. Immunohistochemical investigations of mdr-1, hMLH1/2 were performed on paraffin-embedded tissue section of the primary tumour and the resected lymph nodes using monoclonal, commercially available antibodies. Staining was analysed according to a semiquantitative scoring system; furthermore, detailed morphometry was performed. Preoperative serum and clinical parameters were assessed to predict necrosis/fibrosis or teratoma in residual tumors. Statistical analysis was performed by uni- and multivariate analysis to correlate data with histology of the RTR specimens. Parameters were statistically significant if p<0.05. Results: A total of 122 patients (65.9%) had necrosis, 23 patients (12.4%) and 40 patients (21.6%) had viable cancer and mature teratoma, resp. After multivariate analysis pre-chemotherapeutic AFP-levels, tumor size before RTR, mature teratoma in the primary and mdr-1 expression in the primary were independent predictors of final necrosis. Positive predictive values were 74%, 76%, 78% and 88% resp., sensitivity was 81%, 52.8%, 65% and 86%, resp.; specificity was 59%, 79.3%, 81% and 90% resp.. Nonseminomatous elements demonstrated a significantly higher staining intensity for hMLH1 than seminomas, whereas staining intensity for hMLH2 was lower (p=0.03). IHC for hMLH1/2 of GCT with necrosis was higher as compared to GCT exhibiting mature teratoma or vital cancer approaching statistical significance (p=0.07). Conclusions: Pre-chemotherapy AFP levels < 15 ng/ml and a residual mass < 2 cm are associated with a favourable histology in the RTR specimen. The addition of mdr-1 expression in the primary NSGCT improves sensitivity to 88% and represents a clinically useful prediction marker. No significant financial relationships to disclose.

Second-Look Surgery for Intracranial Germ Cell Tumors

Neurosurgery ◽  
2015 ◽  
Vol 76 (6) ◽  
pp. 658-662 ◽  
Author(s):  
Hideki Ogiwara ◽  
Chikako Kiyotani ◽  
Keita Terashima ◽  
Nobuhito Morota
Keyword(s):  
Germ Cell ◽  
Tumor Markers ◽  
Mature Teratoma ◽  
Germ Cell Tumors ◽  
Residual Tumor ◽  
Complete Response ◽  
Mixed Germ Cell Tumor ◽  
Second Look ◽  
Intracranial Germ Cell Tumors ◽  
Atypical Cells

Abstract BACKGROUND: The role of second-look surgery in intracranial germ cell tumors (GCTs) needs to be reviewed. OBJECTIVE: To present our experience of second-look surgery in patients with intracranial GCTs who showed less than complete response despite normalizing or decreasing tumor markers after chemotherapy. METHODS: Retrospective review of 7 patients who underwent second-look surgery for an intracranial GCT was performed. RESULTS: Of 23 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and August 2013, 7 patients (30%) underwent second-look surgery. The mean age was 9.4 years. The initial diagnoses were mixed germ cell tumor in 5 and immature teratoma in 2. Second-look surgery was performed after 1 to 3 courses of chemotherapy. Magnetic resonance imaging at the surgery demonstrated increasing residual tumor in 4 and stable residual tumor in 3. Tumor markers were normalized in 5 and nearly normalized in 2. Gross total resection was achieved in all patients. Histopathology at second-look surgery revealed mature teratoma in 5, fibrosis with atypical cells in 1, and fibrosis in 1. All patients subsequently underwent additional chemoradiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence, with a mean follow-up of 48 months. CONCLUSION: Second-look surgery plays an important role in the treatment of intracranial GCTs. Surgery may be encouraged at a relatively early phase after chemotherapy when the residual tumor increases or does not change size despite normalized or nearly normalized tumor markers in order to achieve complete resection and improve outcome.

scholarly journals GCT-14. SECOND-LOOK SURGERY FOR INTRACRANIAL GERM CELL TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii330-iii330
Author(s):  
Hideki Ogiwara
Keyword(s):  
Germ Cell ◽  
Tumor Markers ◽  
Mature Teratoma ◽  
Germ Cell Tumors ◽  
Residual Tumor ◽  
Complete Response ◽  
Immature Teratoma ◽  
Total Resection ◽  
Mixed Germ Cell Tumor ◽  
Second Look

Abstract OBJECTIVE The authors present their experiences of second-look surgery in patients with intracranial GCTs who showed less than complete response despite normalizing or decreasing tumor markers after chemotherapy. METHODS Retrospective review of 14 patients who underwent second-look surgery for an intracranial GCT was performed. RESULTS Of 40 consecutive patients with newly diagnosed intracranial GCTs treated between August 2003 and 2019, 14 patients (35%) underwent second-look surgery. The mean age was 9.2 years. The initial diagnoses were mixed germ cell tumor in 6, immature teratoma in 4, yolk sac tumor in 2, and germinoma 2. Second-look surgery was performed after 1–3 courses of chemotherapy. Magnetic resonance imaging (MRI) at the surgery demonstrated increasing residual tumor in 8 and stable residual tumor in 6. Tumor markers were normalized in 10 and nearly-normalized in 4. Gross total resection was achieved in 12 patients and near-total resection in 2. Histopatholgy at second-look surgery revealed mature teratoma in 6, immature teratoma in 3, fibrosis with atypical cells in 2, and fibrosis in 3. Eleven patients subsequently underwent additional chemo-radiation therapy according to the initial diagnosis. All patients are alive with no evidence of recurrence with a mean follow-up of 69 months. CONCLUSIONS Second-look surgery plays an important role in the treatment of intracranial GCTs. Surgery may be encouraged at a relatively early phase after chemotherapy when the residual tumor increases or does not change the size despite normalized or nearly-normalized tumor markers in order to achieve complete resection and improve the outcome.

scholarly journals Reduced and Compressed Cisplatin-Based Chemotherapy in Children and Adolescents With Intermediate-Risk Extracranial Malignant Germ Cell Tumors: A Report From the Children’s Oncology Group

2017 ◽  
Vol 35 (11) ◽  
pp. 1203-1210 ◽  
Author(s):  
Furqan Shaikh ◽  
John W. Cullen ◽  
Thomas A. Olson ◽  
Farzana Pashankar ◽  
Marcio H. Malogolowkin ◽  
...  
Keyword(s):  
Germ Cell ◽  
Children And Adolescents ◽  
Statistical Significance ◽  
Germ Cell Tumors ◽  
Stage I ◽  
Stage Ii ◽  
Intermediate Risk ◽  
Historical Cohort ◽  
Number Of Cycles ◽  
Malignant Germ Cell Tumors

Purpose To investigate whether event-free survival (EFS) can be maintained among children and adolescents with intermediate-risk (IR) malignant germ cell tumors (MGCT) if the administration of cisplatin, etoposide, and bleomycin (PEb) is reduced from four to three cycles and compressed from 5 to 3 days per cycle. Patients and Methods In a phase 3, single-arm trial, patients with IR MGCT (stage II-IV testicular, II-III ovarian, I-II extragonadal, or stage I gonadal tumors with subsequent recurrence) received three cycles of PEb. A parametric comparator model specified that the observed EFS rate should not be significantly < 92%. As recommended for trials that test a reduction of therapy, a one-sided P value ≤ .10 was used to indicate statistical significance. In a post hoc analysis, we also compared results to the EFS rate of comparable patients treated with four cycles of PEb in two prior studies. Results Among 210 eligible patients enrolled from 2003 to 2011, 4-year EFS (EFS4) rate was 89% (95% confidence interval, 83% to 92%), which was significantly lower than the 92% threshold of the comparison model ( P = .08). Among 181 newly diagnosed patients, the EFS4 rate was 87%, compared with 92% for 92 comparable children in the historical cohort ( P = .15). The EFS4 rate was significantly associated with stage (stage I, 100%; stage II, 92%; stage III, 85%; and stage IV, 54%; P < .001). Conclusion The EFS rate for children with IR MGCT observed after three cycles of PEb was less than that of a prespecified parametric model, particularly for patients with higher-stage tumors. These data do not support a reduction in the number of cycles of PEb from four to three. However, further investigation of a reduction in the number of cycles for patients with lower-stage tumors is warranted.

scholarly journals MPC-08 CLINICOPATHOLOGICAL ANALYSIS OF 12P GAIN IN INTRACRANIAL GERM CELL TUMORS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii23-ii23
Author(s):  
Kaishi Satomi ◽  
Hirokazu Takami ◽  
Shintaro Fukushima ◽  
Yoichi Nakazato ◽  
Shota Tanaka ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumor ◽  
Copy Number ◽  
Mature Teratoma ◽  
Methylation Status ◽  
Germ Cell Tumors ◽  
Copy Number Variations ◽  
Cell Tumor ◽  
Testicular Germ Cell ◽  
Intracranial Germ Cell Tumor

Abstract BACKGROUND Gain of short arm of chromosome 12 (12p) is commonly observed in testicular germ cell tumors (tGCTs). 12p gain is also frequently seen in intracranial GCTs (iGCTs). However, little is known about the clinical significance of 12p gain in iGCTs. MATERIALS AND METHODS We have collected over 200 fresh frozen tissue samples of iGCTs through the Intracranial Germ Cell Tumor Genome Analysis Consortium in Japan. Firstly, we analyzed DNA methylation status in 83 iGCTs, 3 seminomas and 6 normal control samples using Infinium Human Methylation 450K BeadChip array (Illumina, CA). Idat files were processed using R (Version 3.5.3) and minfi package (1.30.0) to generate copy number variations. Compared with average genome-wide copy number level, 12p gain was determined. Then, 58 iGCTs with clinicopathological information were analyzed for progression-free survival (PFS) and overall survival (OS). Those tumors that consist of only either germinoma and/or mature teratoma components were classified as Favorable Histology (FH) and all the others that contains malignant histological components were classified as Unfavorable Histology (UFH). RESULT 12p gain was observed in 100% (3/3) of seminoma, 13.6% (3/22) of germinoma, 16.7% (1/6) of mature teratoma, 25% (1/4) of immature teratoma, 55% (11/20) of mixed germ cell tumor, 100% (4/4) of yolk sac tumor, 100% (1/1) of embryonal carcinoma, and 100% (1/1) of choriocarcinoma. In total, 44.6% (37/83) of iGCT showed 12p gain. Regarding histological classification, the 12p gain rate in UFH (72%, 18/25) was significantly higher than that in FH (12.1%, 4/33, P&lt;0.01). Both PFS and OS were significantly worse in iGCTs with 12p gain (PFS: P=0.027, OS: P=0.0012). DISCUSSION 12p gain can be a molecular marker to predict prognosis and histological malignancy in iGCTs.

scholarly journals Applying Radiomics to Predict Pathology of Postchemotherapy Retroperitoneal Nodal Masses in Germ Cell Tumors

2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jeremy Lewin ◽  
Paul Dufort ◽  
Jaydeep Halankar ◽  
Martin O’Malley ◽  
Michael A.S. Jewett ◽  
...  
Keyword(s):  
Germ Cell ◽  
Mature Teratoma ◽  
Germ Cell Tumors ◽  
Area Under The Curve ◽  
Prediction Algorithm ◽  
Support Vector ◽  
Clinical Predictors ◽  
Testicular Germ Cell ◽  
Clinical Variables ◽  
Computed Tomography Images

Purpose After chemotherapy, approximately 50% of patients with metastatic testicular germ cell tumors (GCTs) who undergo retroperitoneal lymph node dissections (RPNLDs) for residual masses have fibrosis. Radiomics uses image processing techniques to extract quantitative textures/features from regions of interest (ROIs) to train a classifier that predicts outcomes. We hypothesized that radiomics would identify patients with a high likelihood of fibrosis who may avoid RPLND. Patients and Methods Patients with GCT who had an RPLND for nodal masses > 1 cm after first-line platinum chemotherapy were included. Preoperative contrast-enhanced axial computed tomography images of retroperitoneal ROIs were manually contoured. Radiomics features (n = 153) were used to train a radial basis function support vector machine classifier to discriminate between viable GCT/mature teratoma versus fibrosis. A nested 10-fold cross-validation protocol was used to determine classifier accuracy. Clinical variables/restricted size criteria were used to optimize the classifier. Results Seventy-seven patients with 102 ROIs were analyzed (GCT, 21; teratoma, 41; fibrosis, 40). The discriminative accuracy of radiomics to identify GCT/teratoma versus fibrosis was 72 ± 2.2% (area under the curve [AUC], 0.74 ± 0.028); sensitivity was 56.2 ± 15.0%, and specificity was 81.9 ± 9.0% ( P = .001). No major predictive differences were identified when data were restricted by varying maximal axial diameters (AUC range, 0.58 ± 0.05 to 0.74 ± 0.03). The prediction algorithm using clinical variables alone identified an AUC of 0.76. When these variables were added to the radiomics signature, the best performing classifier was identified when axial masses were limited to diameter < 2 cm (accuracy, 88.2 ± 4.4; AUC, 0.80 ± 0.05; P = .02). Conclusion A predictive radiomics algorithm had a discriminative accuracy of 72% that improved to 88% when combined with clinical predictors. Additional independent validation is required to assess whether radiomics allows patients with a high predicted likelihood of fibrosis to avoid RPLND.

scholarly journals Impact of Teratoma on the Cumulative Incidence of Disease-Related Death in Patients With Advanced Germ Cell Tumors

2019 ◽  
Vol 37 (26) ◽  
pp. 2329-2337 ◽  
Author(s):  
Samuel A. Funt ◽  
Sujata Patil ◽  
Darren R. Feldman ◽  
Robert J. Motzer ◽  
Dean F. Bajorin ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cumulative Incidence ◽  
Mature Teratoma ◽  
Germ Cell Tumors ◽  
Adverse Outcomes ◽  
Term Survival ◽  
Risk Status ◽  
Primary Tumors ◽  
Platinum Based Chemotherapy

PURPOSE In men with metastatic germ cell tumors (GCTs), risk-directed treatment is determined, in part, by a distinction between seminoma and nonseminomatous GCT (NSGCT). The importance of NSGCT cell type is uncertain. We evaluated the long-term impact of teratoma on survival in patients with NSGCT. METHODS Prechemotherapy, primary tumors from patients who received platinum-based chemotherapy were studied, and the histology was confirmed by a genitourinary pathologist. The cumulative incidence of disease-related death (CIDD) was the primary end point, and a competing-risk analysis was performed. RESULTS Tumors were available from 232 patients, including 193 with NSGCT. An element of teratoma was present in 82 NSGCT primary tumors (42%). With a median follow-up of 17 years (range, 0.3 to 35 years), 58 patients with NSGCT died, 47 as a result of GCT and 11 as a result of other causes. Most GCT deaths occurred within the first 5 years and were associated with pretreatment risk status ( P < .001). Death as a result of other causes rose steadily after 15 years and was not associated with risk status ( P = .66). A higher CIDD was observed in patients who had NSGCT with teratoma than those with NSGCT without teratoma and seminoma (5-year CIDD rate, 27.4%, 17.4%, and 10.3%, respectively; P = .03). A higher CIDD was observed in patients who had NSGCT with mature teratoma compared with those with either NSGCT with immature teratoma or NSGCT without teratoma (5-year CIDD rate, 38.1%, 19.9%, and 17.4%, respectively; P = .01). CONCLUSION The presence of teratoma, particularly mature teratoma, in an NSGCT primary tumor is associated with a higher CIDD, consistent with the hypothesis that differentiation is associated with adverse outcomes. Death as a result of non-GCT causes is not associated with risk status and must be separated from GCT death when evaluating long-term survival.

scholarly journals Intracranial teratomas in children: the role and timing of surgical removal

2008 ◽  
Vol 2 (5) ◽  
pp. 331-338 ◽  
Author(s):  
Rémy Noudel ◽  
Mathieu Vinchon ◽  
Patrick Dhellemmes ◽  
Claude Fabien Litré ◽  
Pascal Rousseaux
Keyword(s):  
Germ Cell ◽  
Mature Teratoma ◽  
Tumor Resection ◽  
Germ Cell Tumors ◽  
Timing Of Surgery ◽  
Surgical Removal ◽  
Primary Therapy ◽  
Large Tumor ◽  
Oncological Treatment ◽  
Malignant Germ Cell Tumors

Object In this study, the authors report their experience with the surgical treatment of intracranial teratomas with an emphasis on the indications for delayed resection after oncological treatment. Methods The authors retrospectively reviewed the cases of 14 children with intracranial teratomas. The mean age at diagnosis was 10.5 years (range 2 days–18 years), and 11 patients were male. The final histological analysis revealed pure mature teratoma in 5 cases, mixed teratoma with germinoma in 3 cases, and nongerminomatous malignant germ cell tumor in 6 cases. Thirteen patients underwent tumor resection, and these patients were divided into 2 subgroups according to the timing of surgery. In Group A, 10 patients underwent resection as the primary treatment because no tumor markers were detected in 4 patients, a teratomatous component was revealed on biopsy sampling in 3 patients, and a large tumor volume in 3 patients. In Group B, 3 patients underwent removal of residual pure mature teratoma after oncological treatment. Results Seven of the 8 patients (87.5%) with pure mature teratomas or with mixed teratoma and germinoma are currently alive (mean follow-up of 9 years); the eighth patient died of postoperative meningitis. Two of the 6 patients (33%) with mixed nongerminomatous malignant germ cell tumors died of tumor progression regardless of the timing of surgery. Conclusions The results of this study support the belief that microsurgical removal is the only effective treatment for intracranial teratomas. Surgery may be performed as the primary therapy when there is evidence of a noninvasive teratoma, and as a secondary therapy if there is only a partial response to neoadjuvant therapy or if progression is observed in mixed malignant germ cell tumors.

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