Induction Chemotherapy Reduces Radiation Therapy Dose and Volume in the Treatment of Intracranial Germinoma: Results of the SMC-G13 Trial.

PURPOSE: We performed a prospective single-arm trial (NCT02782754) to explore the feasibility of reducing radiation therapy (RT) dose when induction chemotherapy is combined in the treatment of intracranial germinoma with beta-human chorionic gonadotropin levels <200 mIU/mL. METHODS AND MATERIALS: All patients aged 3 to 35 years from November 2012 to June 2018 were eligible for this study. Four cycles of induction chemotherapy were given before RT. Carboplatin/etoposide and cyclophosphamide/etoposide regimens were used in alternation every 3 weeks. A dose of 18 Gy of craniospinal RT for metastatic tumors, whole brain RT for basal ganglia tumors, or otherwise whole ventricular RT followed by 12.6 Gy of boost RT to the primary tumor bed was administered after induction chemotherapy. The primary endpoint of this study was progression-free survival. RESULTS: A total of 41 consecutive patients were enrolled (location: suprasellar in 12, pineal in 12, both suprasellar and pineal in 11, and basal ganglia in 6 patients). Eleven patients had leptomeningeal seeding. Toxicity during chemotherapy was mild, except for bone marrow suppression. Tumor status after induction chemotherapy was complete response in 33 patients and partial response in 8. All but 2 patients completed the scheduled treatment. All patients but 1 remained event free during a median follow-up of 3.4 (range, 0.3-7.0) years from diagnosis. The 1 patient experienced relapse and died of tumor bleeding. Late effects were not significant except for neuroendocrine dysfunction already present at diagnosis. Vertical growth and cognitive function were not significantly disturbed by treatment. CONCLUSIONS: This study showed the feasibility of reducing RT dose/volume with induction chemotherapy in pathologically pure germinoma with elevated beta-human chorionic gonadotropin levels up to 200 mIU/mL.

Intracranial Pure Germinoma With Optic Nerve Infiltration.

A 19-year-old man presented with a 3-year history of episodic headaches, right hemiparesis, and progressive vision loss in both eyes. Initially, extensive laboratory testing was unrevealing. MRI later demonstrated progressive enlargement and enhancement of the left optic nerve poorly correlated with the timing of his clinical manifestations. There was no clinical or radiological response to treatment with corticosteroids, mycophenolate mofetil, or rituximab administered empirically for possible inflammatory processes. Later in the disease course, he developed diabetes insipidus (DI), worsening vision to light perception bilaterally, severe cognitive decline, and spastic quadriparesis. Cerebrospinal fluid (CSF) beta human chorionic gonadotropin (ß-hCG) was elevated. Eventually, a left optic nerve biopsy was performed, which was consistent with an intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Although rare, intracranial germ cell tumors can primarily involve the anterior visual pathways and should be considered in the setting of DI and elevated CSF ß-hCG.

Intracranial Germ Cell Tumors in Adolescents and Young Adults: A 40-Year Multi-Institutional Review of Outcomes.

PURPOSE: The aim of this study was to determine the practice patterns and outcomes of intracranial germ cell tumors (IGCT) in adolescents and young adults according to different therapeutic approaches. METHODS AND MATERIALS: One-hundred twelve patients with IGCT aged 15 to 39 years were managed at either XX or the XY center from 1975 to 2015. The charts were retrospectively reviewed and data collected. RESULTS: Median duration of follow-up was 8.3 years. Ninety-four patients had germinomas, and 18 had nongerminomatous germ cell tumors (NGGCT). The primary disease sites were pineal gland (37 of 94 germinoma, 14 of 18 NGGCT) and suprasellar region (23 of 94 germinoma, 2 of 18 NGGCT). Eleven patients with germinoma (12%) and 2 patients with NGGCT (11%) had radiographic spinal metastases or positive lumbar cerebrospinal fluid cytology. Event-free survival (EFS) was 84% and overall survival (OS) was 90% at 10 years for germinoma; EFS was 71% and OS was 86% at 10 years for NGGCT. For patients with germinoma, 10-year EFS was 100% after craniospinal radiation therapy (CSRT) with chemotherapy (N = 10); 100% after whole-ventricular radiation therapy (WVRT), whole-brain radiation therapy (WBRT), or focal radiation therapy (FRT) with chemotherapy (N = 22); 90% after CSRT alone (N = 46); and 41% after WVRT, WBRT, or FRT alone (N = 16) (P < .0005). Ten-year OS was 100%, 100%, 90%, and 72%, respectively (P = .032). For patients with NGGCT, 10-year EFS was 80% after CSRT, WBRT, or WVRT plus chemotherapy (N = 10) versus 58% after FRT plus chemotherapy (N = 8) (P = .31); 10-year OS was 90% versus 58%, respectively (P = .16). CONCLUSIONS: We report excellent overall outcomes according to treatment approach in the largest study of IGCT in adolescents and young adults to our knowledge. EFS and OS were inferior after non-CSRT without chemotherapy in germinoma.

Bifocal germinomas in the pineal region and hypothalamo-neurohypophyseal axis: Primary or metastasis?

Whether bifocal germinomas (BFGs) synchronously presenting within the pineal region and the hypothalamo-neurohypophyseal axis (HNA) are primary germinomas of dual-origin remains to be elucidated. We analyzed MRI images and clinical features of 95 neurohypophyseal germinomas and 21 BFG patients and developed a tentative definition of the BFGs. We found dual-primary BFGs (true BFGs) do exist. The fundamental difference between primary and metastatic HNA germinomas was the direction of tumor growth. For a true BFG, the primary HNA tumor grew from the neurohypophysis toward the hypothalamus and almost invaded the whole pituitary stalk. For a false BFG (primary pineal germinoma with HNA metastasis), the metastatic HNA tumor first appeared at the third ventricular floor (TVF), grew toward the neurohypophysis, but commonly did not invade the inferior pituitary stalk. Compared to false BFGs, true BFGs commonly had diabetes insipidus as the first symptom, dysfunction of the anterior pituitary, no high-intensity MRI signal at the posterior pituitary, a larger extension of the HNA tumor, and fewer numbers of remote lesions from cerebrospinal fluid seeding. Accordingly, 12.8% (12/96) of our germinoma patients had true BFGs, and of these, 58.3% (7/12) were free of remote metastases and warranted treatment with limited radiotherapy. True BFGs with remote metastases and all false BFGs should be treated with craniospinal irradiation. We provided evidence for the diagnosis of true BFGs that is useful for radiotherapy strategy, suggesting that the existence of metastasis to other locations is not a diagnostic criterion for a true BFG.

The necessity of long-term follow-up including spinal examination after successful initial treatment of intracranial germinoma: case reports.

INTRODUCTION: Intracranial germinomas seldom recur at spinal space following whole-brain or whole-ventricular (WV) radiotherapy. The majority of the spinal recurrence takes place within 5 years after treatment; therefore, late spinal failure beyond 5 years after successful initial treatment is rare. CASE PRESENTATIONS: We describe the cases of two patients with intracranial germinoma, who developed spinal recurrence 7 and 9 years after the initial treatment with WV radiotherapy combined with and without chemotherapy, respectively. In both cases, spinal recurrent tumors were histologically diagnosed as germinoma and they were successfully treated with chemotherapy and local radiotherapy without tumor recurrence for 11 years and 11 months, respectively. CONCLUSION: Intracranial germinomas may potentially present with spinal recurrence many years after successful initial WV radiotherapy. Physicians must be aware of patients' symptoms during the clinical examination. Regular long-term monitoring, including spinal examination, is necessary for 5-10 years or longer.

Germinoma recurrence in the conus medullaris 12 years after remission of primary intracranial lesion in the pituitary.

Intracranial germinomas are rare primary central nervous system tumours that are highly sensitive to radiotherapy and chemotherapy. Recurrences are infrequent, with the majority occurring within 5 years. Although multidisciplinary treatments have resulted in good event-free survival, long-term outcomes, over decades, are relatively poorly reported. We present a rare case of a recurrence in the conus medullaris 12 years after complete remission of the primary pituitary germinoma. To the best of our knowledge, this represents the first case of a significantly delayed spinal recurrence, occurring at a very distant and uncommon site, from the primary tumour. This case highlights the importance of long-term follow-up, even after complete remission, in order to identify and limit disability from late spinal recurrences in a relatively young patient population. We consider the literature regarding identifying high risk patients, and the role of craniospinal irradiation in limiting late spinal recurrences.

Is there a limit for the laparoscopic approach of a retroperitoneal residual mass postchemotherapy?

OBJECTIVES: Rescue lymphadenectomy for testicular cancer is a complex surgery, with a high number of complications. The laparoscopic approach appears to offer faster recovery and improved quality of life compared with open surgery. The aim of our study is to report on our experience and to define whether there is a limit (oncological, anatomical or technical) for laparoscopic management. MATERIAL AND METHODS: A retrospective study was conducted of 15 patients who underwent laparoscopic retroperitoneal lymphadenectomy after chemotherapy. In addition to epidemiological and oncologic variables, we analyzed the mean surgical time, intraoperative and postoperative complications, the mean hospital stay and the mean follow-up time. RESULTS: The mean surgical time was 294 minutes (range, 180-240). There were 4 large-vessel vascular lesions, all of which were large-volume retroperitoneal masses, with diameters >7 cm. The rate of postoperative complications was 33%; there was only 1 case of Clavien >III. The mean hospital stay was 5.38 days (range, 2-9), and the mean patient follow-up was 28.9 months (range, 1-79). There was no recurrence in any of the cases. CONCLUSIONS: The laparoscopic approach is an oncologically safe option for the rescue treatment of testicular cancer. The complex location of these masses entails the onset of severe intraoperative complications. We have observed a clear relationship between vascular complications and large masses (>7 cm). We therefore believe that it would be appropriate to establish a limit on the size for laparoscopic treatment.

Unusual behaviour of a pineal germinoma mimicking neurosarcoidosis and metastasising along the endoscopic route.

A previously healthy man underwent endoscopic biopsy for a suspected pineal germinoma. Histology and immunohistochemistry did not confirm the preoperative diagnosis, and neurosarcoidosis was hypothesised because of the presence of granulomatous reaction. The patient remained in good health for 3 years and was still asymptomatic when a control MRI showed metastasis implantation along the endoscopic route. A redobiopsy provided the diagnosis of germinoma, but was complicated by severe ventricular haemorrhage requiring emergency clot excision. Postoperative clinical conditions were so severe that the treatment of germinoma was postponed. Three months later, repeated MRI showed tumour progression. Chemotherapy promoted good tumour regression so that the treatment was completed by radiation therapy. The tumour completely disappeared on MRI, but the patient remained severely disabled because of the haemorrhage.

Metastasis germinomas of the external acoustic meatus: in a 19-year-boy: a case report.

BACKGROUND: The external acoustic meatus metastasis of germinomas is a rare event. CASE PRESENTATION: we describe a 19-year-old boy with stuffiness and earplug of the left ear but no other symptoms. The whole body F-18 FDG PET/CT and the brain MRI are performed and demonstrated a germinoma in the pineal gland and vermis cerebellum region and in the right of thalamus. Photomicrograph showing marked infiltration of lymphoplasma cells and macrophages including giant cells. Immunohistochemical analysis results demonstrated the tumor cells are strongly positive for CD117 and PLAP. The final diagnosis was germinoma and all adjuvant therapy was achieved. CONCLUSION: Although the external acoustic meatus metastasis of germinomas is rare, the diagnosis should be taken into serious consideration in order to improve. In addition, F-18 FDG PET/CT was very useful in diagnosis primary disease and excluding distant metastases. To our knowledge, this is the first published report of this type of case.

Pathological findings after primary chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection for advanced germ cell tumours.

OBJECTIVE: To determine the differential response to systemic chemotherapy in patients undergoing simultaneous orchidectomy and retroperitoneal lymph node dissection (RPLND) after chemotherapy for metastatic testicular cancer. PATIENTS AND METHODS: Patients who underwent simultaneous RPLND and orchidectomy after chemotherapy were identified from our clinical databases. Postoperative pathological findings and patient characteristics were reviewed. RESULTS: In all, 42 patients were identified. After chemotherapy, necrosis, teratoma and cancer were identified in 25 (59.5%), 14 (33.3%) and three (7.1%) RPLN specimens and 15 (35.7%), 15 (35.7%) and 12 (28.6%) orchidectomy specimens respectively. Of the 25 patients with necrotic RPLN specimens 12 (48.0%) had active disease within the orchidectomy specimen (eight invasive cancer and four mature teratoma). The overall histological discordance rate was 38.1%. Findings in the orchidectomy specimens were more aggressive than those in the RPLN specimens (i.e. cancer worse than teratoma, which is worse than necrosis) in 33.3%. CONCLUSIONS: There is significant disparity between orchidectomy and RPLND findings with viable tumour appearing frequently in the testis despite tumour-free RPLNs. These findings support completion orchidectomy as part of advanced testicular germ cell treatment.

The enigma of bifocal germ cell tumors in the suprasellar and pineal regions: synchronous lesions or metastasis?

OBJECT: Intracranial germ cell tumors (GCTs) frequently present with bifocal lesions in both the suprasellar and pineal areas. The pathogenesis of these bifocal GCTs has been the subject of controversy. Bifocal GCTs may be caused by synchronous tumors or by metastatic spread of tumor cells from one site to the other. The prognosis associated with bifocal GCTs has also been a cause of concern. METHODS: The authors constructed a single-institution patient cohort comprising 181 patients with intracranial GCTs. The clinical characteristics of bifocal GCTs were compared with those of suprasellar and pineal GCTs. RESULTS: Bifocal GCTs were observed in 23 patients (12.8%). Eighteen patients presented with bifocal GCTs that were diagnosed as germinomas, but 5 patients exhibited mixed GCTs. Analyses of age distributions and comparisons of tumor sizes were compatible with a model of a metastatic origin of bifocal GCTs. Eleven patients (47.8%) presenting with bifocal GCTs exhibited tumor seeding at presentation. Tumor seeding was significantly associated with bifocal lesions (p < 0.001). Patients with bifocal germinomas showed significantly shorter event-free survival and overall survival than did those presenting with germinomas from a single site of origin. CONCLUSIONS: Bifocal GCTs are not restricted to germinomas, as had been previously reported, but do include mixed GCTs. The authors hypothesize that bifocal GCTs may result from the metastatic spread of suprasellar or pineal GCTs. The bifocal presentation of germinomas may be a poor prognostic sign and should alert clinicians to the possibility of a disseminated disease.

Effective radiotherapy cured cauda equina syndrome caused by remitted intracranial germinoma depositing.

Cauda equina syndrome (CES) in children is very rare and can permanently disable. A remitted intracranial germinoma depositing on the spinal cord, leading to CES, has never been reported. We discuss the case of a 10-year-old girl who presented with sudden ataxia, low back pain, sensory deficits of the left lower extremity, and difficulty urinating and defecating 7 months after totally remitted intracranial germinoma postintracranial surgery and cranial irradiation. Magnetic resonance imaging (MRI) of the brain and spine showed multiple intradural extramedullary homogeneous masses from the cervical to lumbar levels, compressing the conus medullaris and cauda equina. After emergent craniospinal irradiation, the patient's neurologic symptoms dramatically subsided. A remitted intracranial germinoma depositing on her spinal cord could be the cause of CES. Early identification and a proper craniospinal irradiation may halt the progression of symptoms.

Intramedullary recurrence of germinoma in the spinal cord 15 years after complete remission of a pineal lesion.

The authors present a case of germinoma that was initially found in the pineal region and recurred 15 years later in the intramedullary cervical spinal cord after intensive chemo- and radiotherapy and diagnosis of complete remission. This 28-year-old man initially presented with seizures. Hydrocephalus and a pineal tumor were found on radiological examination, and partial resection of the tumor was performed. Histological diagnosis showed a pure germinoma. Following surgery, the patient received a combination of chemo- and radiotherapy, and a complete remission was shown. However, after 15 years of follow-up, he presented with gait disturbances. Spinal MRI showed an intramedullary mass lesion in the cervical spinal cord. The cervical lesion was biopsied, and histological examination again revealed a pure germinoma. With germinomas, the possibility of a drop metastasis from an intracranial lesion to the spinal cord must be considered during follow-up. However, in the present case, analysis of a CSF sample showed no abnormalities as in previously published cases. In recent years, multidisciplinary treatments have demonstrated good event-free survival rates in cases of pure germinomas, but long-term outcomes over the decades are not fully known. Continual follow-up of such cases is recommended even after complete remission has been achieved.

Neuronavigation-guided endoscopic management of a pineal region tumour with obscured floor of the third ventricle: case report.

BACKGROUND: Shunt surgery is frequently chosen to manage periventricular metastasis of pineal region tumours which obscured the floor of the third ventricle. However, this procedure falls short due to distant metastasis. Neuronavigation-guided endoscopic surgery offers a viable alternative. PATIENT: A 17-year-old man became symptomatic from widespread periventricular metastasis of a pineal region tumour which completely obscured the floor of the third ventricle. RESULTS: Endoscopic tumour biopsy followed by neuronavigation-guided endoscopic third ventriculotomy was performed successfully. CONCLUSION: This case report emphasizes the value of neuronavigation-guided endoscopic third ventriculostomy as a feasible surgical alternative for pineal region tumours with widespread periventricular metastasis that obscure the third ventricular floor.

Intra-abdominal metastasis of an intracranial germinoma via ventriculo-peritoneal shunt in a 13-year-old female.

A 13-year-old patient presented with massive intra-abdominal metastasis and spontaneous acute tumour lysis syndrome, 17-months after VP shunt placement for metastatic pineal germinoma treated with cranio-spinal-irradiation. Hyperhydration/rasburicase improved renal function, allowing chemotherapy with subsequent surgery. The patient remains event-free 34-months later. Risk of intra-abdominal metastasis from VP shunts is discussed.

SenseCam as a rehabilitation tool in a child with anterograde amnesia.

We present the case of a 13-year-old boy, CJ, with profound episodic memory difficulties following the diagnosis of a metastatic intracranial germ cell tumour and subsequent treatment with radiotherapy and chemotherapy. At the core of this study is the first application of SenseCam to a child with severe memory impairment. CJ was taken for a walk while he was wearing SenseCam. This included visiting four different locations. We manipulated the number of locations he could review on SenseCam "films" and then tested recognition memory (forced choice) for both reviewed and non-reviewed locations. We also collected his justifications for the choices he made. Our results indicate that repeated viewings of SenseCam images support the formation of personal semantic memories. Overall our results suggest that the use of SenseCam in memory rehabilitation extends beyond supporting episodic memory and recollection, and supports the feasibility of its use with children who have marked memory difficulties.

Pure germinoma of the pineal gland with synchronous spinal dissemination--case report.

An 11-year-old boy presented with pineal pure germinoma with spinal dissemination manifesting as a 1-month history of ocular motility disturbance and a history of abnormal sensations in the left leg persisting for several months. His past medical history was unremarkable. Craniospinal magnetic resonance imaging showed an enhanced tumor in the pineal gland and widespread leptomeningeal dissemination in the spinal canal. Biopsy of the pineal tumor was performed. Histological examination revealed a pure germinoma. Chemotherapy with carboplatin and etoposide in combination with radiotherapy induced complete remission of the tumors. He regained normal eye movement and sensation in his left leg during the chemotherapy period. Germinomas with dissemination are generally more malignant and refractory than solitary germinomas, but this patient showed a strong response to chemoradiotherapy.

Rete testis invasion by malignant germ cell tumor and/or intratubular germ cell neoplasia: what is the significance of this finding?

Pathologic stage and postsurgical treatment guidelines of malignant germ cell tumors, currently take into account angiolymphatic invasion, degree of extra testicular invasion, and serum tumor marker levels. The significance of rete testis invasion by malignant germ cell tumors or intratubular germ cell neoplasia however remains controversial. A search through the surgical pathology and expert consultation files at our institution from 2002 to 2009 was made for malignant germ cell tumors and intratubular germ cell neoplasia in orchiectomy specimens. Clinicopathologic data including rete testis status were obtained. Two hundred ninety-two orchiectomy specimens were identified. One hundred thirty-six were associated with malignant germ cell tumors. Mean patient age was 33 years (range, 14-67 years). The mean greatest tumor dimension was 4.1 cm (range, 0.8-18 cm). Fifty-six were pure seminoma (40%), 50 were nonseminomatous malignant germ cell tumors (35%), and 35 were mixed malignant germ cell tumors including a seminoma component (25%). Intratubular germ cell neoplasia was identified in 99 cases (70%). Pathologic stage at presentation was as follows: stage 1, 71 patients (50%); stage 2, 62 patients (45%); stage 3, 2 patients (1%); and indeterminate, 6 patients (4%). Seventy-eight patients had documented rete testis status: rete testis invasion, 41 (53%); no rete testis invasion, 37 (47%). Angiolymphatic invasion was present in 62 cases (44%). Follow-up information was available in 43 patients with known rete testis status. Mean follow-up duration was 43 months (range, 3-65 months). Twenty patients had rete testis invasion, and 23 patients had no rete testis invasion. Intratubular germ cell neoplasia was present in patients with rete testis invasion in 18 cases (90%), compared to only 13 cases (57%) in patients without rete testis invasion, P = .02. Serum markers were elevated in 10 patients (50%) with rete testis invasion compared to only 6 patients (26%) without rete testis invasion, P = .05. The combination of rete testis invasion and angiolymphatic invasion were present in 8 cases and were found to be associated with elevated serum tumor markers in 7 (88%) of the 8 cases, compared to the combination of no invasion of the rete testis and angiolymphatic invasion showing elevated serum tumor markers in 3 (38%) of 8 cases. However, 7 patients (35%) with rete testis invasion developed metastatic disease, and 11 patients (48%) without rete testis invasion developed metastatic disease. Rete testis status should be documented in orchiectomy specimens with malignant germ cell tumors. Intratubular germ cell neoplasia may be the only component of a malignant germ cell tumor involving the rete testis. In this series, elevated tumor markers were more likely associated with angiolymphatic invasion and positive rete testis status. Positive rete testis status does not appear to be an independent predictor of patient outcome.

Population-based study of perioperative mortality after retroperitoneal lymphadenectomy for nonseminomatous testicular germ cell tumors.

OBJECTIVES: To determine whether retroperitoneal lymphadenectomy (RPLND) perioperative mortality (PM) rates reported from a center of excellence (Indiana University: 0% for primary and 0.8% for postchemotherapy RPLND) are applicable to institutions at large. METHODS: We used the data from 882 assessable patients with nonseminomatous testicular germ cell tumor treated with RPLND from 1988 to 1997 accessed from the Surveillance, Epidemiology, and End Results (SEER) database. These data did not include data from Indiana University. The observed PM rates were stratified according to age and SEER stage. RESULTS: The median age at RPLND was 29 years. Of the 882 cases, 435 (49.3%) were performed for localized (Stage I), 380 (43.1%) for regional (Stage II), and 67 (7.6%) for metastatic (Stage III) SEER stage. Of the 882 patients, 7 patients died during the initial 90 days after RPLND, for a 0.8% PM rate. PM increased with increasing age: < or =29 years, 0.0%; 30-39 years, 1.3%; and > or =40 years, 2.7% (chi(2) trend test, P = .002). PM also increased with increasing stage: 0.0% for localized, 0.8% for regional, and 6.0% for metastatic disease (chi(2) trend test, P < .001). CONCLUSIONS: RPLND is associated with virtually no or low PM in patients with localized and regional disease. The PM rates for these 2 groups replicated those of Indiana University. In contrast, the PM rate of 6% for patients with distant metastases implies that RPLND for these higher risk patients should ideally be performed at centers of excellence, with the intent of reducing the PM rate.