Treatment of brain metastases from germ cell tumors

Brain metastases occur in approximately 10% of patients with advanced metastatic germ cell tumors. Patients with nonseminomatous histology, lung metastases, and high β-human chorionic gonadotropin levels are at higher risk for synchronous brain metastases at first diagnosis and for relapsing with brain metastases after successful cisplatin-based chemotherapy. Patients with brain metastases should undergo multimodal treatment strategies, including cisplatin-based combination chemotherapy plus radiotherapy or surgery. However, the optimal combination and sequence of these strategies remain unclear and may differ between subgroups. But in all cases, chemotherapy must be part of treatment, even in patients with isolated cerebral relapse without systemic disease.     

Treatment of malignant germ cell tumors.

In an unselected group of 278 patients with germ cell tumors, disease-free status was obtained in 97% by a treatment program including a surveillance-only strategy for stage I testicular cancer, and low-or high-dose cisplatinum-etoposide treatment for patients with more extensive disease. The overall follow-up period was a median of 40 months (range 20-62 months). At present 100% of patients with stage I disease, 91% with stage II disease, 86% with stage III disease, 75% with extragonadal germ cell tumors, and 3 of 3 patients with germ cell tumors in the ovary are alive and without disease. Among 36 patients treated with high-dose cisplatinum and etoposide there were six toxic deaths, four of them in patients with residual malignant disease. Three patients died of progressive disease. There were no toxic deaths among 54 patients with disseminated disease but without poor prognostic features who were treated with low-dose cisplatinum-etoposide; six of these patients died of progressive disease. It is concluded: 1) that surveillance is a feasible and reasonable strategy for patients with stage I disease; 2) that excellent survival results can be achieved with standard-dose cisplatinum-etoposide in patients with disseminated disease and a favorable prognostic profile; and 3) that disease-free status can be obtained in nearly all patients with poor prognostic features at the expense of significant toxicity. Standardized criteria for selection of patients with poor prognoses are needed. Randomized trials should be carried out to define the role of high-intensity treatment and, finally, measures to decrease or prevent serious toxicity should be explored.     

Therapy-associated secondary tumors in patients with non-germinomatous malignant germ cell tumors

We report three patients with non-germinomatous malignant germ cell tumor (NGMGCT) who developed therapy-associated secondary tumors. They were diagnosed as having NGMGCT by elevated serum levels of α-fetoprotein (AFP), human chorionic gonadotropin (HCG), or β-HCG. Preoperatively, all patients received a combination of etoposide and platinum-based chemotherapy and radiotherapy; neo-adjuvant therapy (NAT) was followed by complete excision of the residual tumor. Postoperatively, all underwent maintenance chemotherapy and all remained free of NGMGCT without recurrence. However, they developed therapy-associated secondary tumors, i.e. glioblastoma, meningioma, or cavernous angioma after 10.1, 9.8, and 8.2 years, respectively. The patient with gliobastoma died one year after its detection. The other two patients are currently alive; the meningioma was completely removed and the cavernous angioma is being monitored without additional treatment. To the best of our knowledge, therapy-associated secondary tumors in patients treated for NGMGCT are rare.     

Decompression of epidural metastases from germ cell tumors with chemotherapy

Summary Epidural cord compression from germ cell tumor metastases is not common. Treatment usually requires high dose corticosteroids with radiation therapy and/or surgical decompression. Three patients with epidural germ cell tumor metastases were treated with cisplatin-based chemotherapy and all three had complete neurologic recovery. Systemic chemotherapy should be considered as initial therapy with corticosteroids for epidural cord compression from metastatic germ cell tumor.Abbreviations DOX Doxorubicin - CYC Cyclophosphamide - CDDP Cisplatin - BLEO Bleomycin - VBL Vinblastine - ETO Etoposide - IFOS Ifosfamide - PROC Procarbazine - VINC Vincristine - ACT D Actinomycin D. Adapted from Friedman [16]     

Brain metastases of malignant germ cell tumors in children and adolescents

BACKGROUND: Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival. METHODS: The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period. RESULTS: Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors. CONCLUSIONS: Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors.     

Neurological complications of malignant germ cell tumors of testis: biology of brain metastases (I).

Central nervous system metastases are a common complication of disseminated germ cell tumors of the testis. They occurred in 16% of 242 patients treated and in 25% of the patients who died in our VAB chemotherapy series. Pulmonary metastases preceded or coincided with the development of brain metastases. The frequency of brain metastases differed with the histology of the primary tumor. They occurred in 13% of pure embryonal carcinomas, 18% of mixed tumors containing embryonal or choriocarcinoma elements, and 83% of pure choriocarcinomas. Embryonal carcinoma and choriocarcinoma were the principle histologies found in brain metastases. Characteristically, pure choriocarcinoma deposits in the brain were multiple (8/9) and cerebellar involvement was common (5/9). Pure embryonal carcinoma CNS metastases were typically single (6/8) or very few and cerebellar involvement was not observed. The interval from the diagnosis of malignancy to the diagnosis of brain metastases was longer for embryonal carcinoma than for pure choriocarcinoma (23 mos. vs. 6.5 mos.). Survival following the diagnosis of brain metastases was poor. There was a tendency toward longer survival for histologically pure embryonal carcinoma deposits in the brain than for the pure choriocarcinomas (6.5 mos. vs. 1 mo.).     

Treatment outcome of patients with extragonadal nonseminomatous germ cell tumors: the Saitama Cancer Center experience

Background

Survival of patients with extragonadal nonseminomatous germ cell tumors remains inferior to that of patients with advanced testicular cancer, although treatment is often the same for both conditions. In addition, the prognosis for nonseminomatous tumors has been shown to be worse than for seminoma.

Methods

Thirteen patients with extragonadal nonseminomatous germ cell tumors were treated between 1998 and 2011; the primary tumors were located in the mediastinum in six and in the retroperitoneum in seven. At initial diagnosis seven patients had distant metastases. According to the IGCCC, eleven patients had poor prognosis and two were intermediate. All 13 patients received cisplatin or carboplatin-based chemotherapy as initial treatment. The patients were further treated by use of a multi-modal strategy which included high-dose chemotherapy, aggressive surgery, and early introduction of salvage regimens.

Results

Complete response was obtained for eight patients. Among these complete responders, one patient remained relapse-free after post-chemotherapy surgical excision of viable cancer tissue. In the course of the chemotherapy, four patients died from cancer progression and one patient died as a result of post-chemotherapeutic sepsis. The other eight patients were alive at the end of the observation period. At the last observation all surviving patients were without evidence of disease. Five-year overall survival for all 13 patients was 62 %, and 5-year cancer-specific survival was 68 %.

Conclusion

Our results indicate that even patients with far-advanced extragonadal nonseminomatous germ cell tumors can be cured by intensive chemotherapy plus surgery.     

Multimodality treatment of patients with liver metastases from germ cell tumors: the role of surgery

BACKGROUND: The presence of liver metastases represents an independent poor risk prognostic factor for survival in patients with germ cell tumors. METHODS: The clinical files of 37 patients who had undergone liver resection for the treatment of disseminated germ cell tumors were reviewed to define the indications for resection of residual liver metastases after chemotherapy in patients with germ cell tumors. The histologic patterns of primary tumor and residual disease were compared. The prognostic factors for survival were studied by univariate analysis. RESULTS: All but 2 of 37 patients underwent complete resection. One patient died of postoperative complications. Thirteen complications occurred in 10 patients. Twelve patients had active residual tumor, 7 patients had mature teratoma, and 18 patients had only necrosis on histologic examination. Twenty-three of 37 patients (62%) were alive with no evidence of disease after a median follow-up of 66 months (range, 31-134 months). Three prognostic factors were found to be significant in the univariate analysis for unfavorable outcome: the presence of pure embryonal carcinoma in the primary tumor, liver metastases measuring > 30 mm in greatest dimension at the time of surgery, and the presence of viable, active residual disease. CONCLUSIONS: Because it is impossible to determine the histologic pattern of residual liver masses after chemotherapy with current imaging tools and percutaneous biopsy, patient selection for liver surgery may be undertaken according to the size of residual liver masses. Patients with masses that measure < or = 10 mm in greatest dimension should be considered for close follow-up, because they have a high probability of necrosis and are at low risk for malignant disease. Male patients with masses that measure > or = 30 mm in greatest dimension represent a high-risk group of patients who are not likely to benefit from liver surgery. Only male patients with masses that measure 10-29 mm in greatest dimension and all female patients with masses that measure > 10 mm in greatest dimension should be considered for liver resection.     

原发性纵隔恶性生殖细胞肿瘤

原发性纵隔恶性生殖细胞肿瘤临床少见,与相应原发性性腺生殖细胞肿瘤的临床表现、诊断、治疗及预后均不相同。以顺铂为基础联合化疗是其主要治疗手段,近年通过综合治疗患者预后明显好转,原发性纵隔精原细胞瘤治愈率高,但非精原细胞瘤预后仍不理想。     

Treatment of malignant ovarian germ cell tumor and sex cord tumors

We outline chemotherapy mainly for malignant ovarian germ cell and sex-cord tumors, based on studies in the literature and our own clinical experiences. With both tumors, PEB treatment is standard adjuvant chemotherapy. With regard to the number of dosage courses, 4 courses are regarded as tolerable after incomplete reduction, and 3 courses as adjuvant treatment after complete extraction. This chemotherapy is effective for preservation of fertility in young patients with malignant ovarian germ cell tumor. In both tumors, some cases show chemotherapy resistance. An effective second-line treatment strategy using a new anticancer agent needs to be established for such cases in the future.     

The significance of atypia within teratomatous metastases after chemotherapy for malignant germ cell tumors

The completely resected teratomatous metastases of 55 patients who had been treated with cisplatin-based combination chemotherapy for non-seminomatous germ cell tumors were reviewed to see if cellular atypia had an effect with respect to recurrent disease. The degree of atypia of the epithelial and mesenchymal elements was assessed on the basis of the cytologic features and mitotic activity. Twenty-three percent of the cases contained high-grade epithelial elements, whereas high-grade mesenchymal elements occurred in 18% of the cases; in addition there were nine cases classified as showing frankly malignant teratomatous elements. The presence of cytologically disturbing epithelial and mesenchymal elements (which, however, lacked an invasive malignant pattern) correlated with an increased incidence of recurrent teratoma compared to less atypical teratomatous elements (23% vs. 6% for epithelial elements, and 18% vs. 9% for mesenchymal elements, respectively). This difference, however, was not statistically significant (P greater than 0.05). There was no correlation between teratomatous atypia and recurrent, non-teratomatous germ cell tumor. The presence of an invasive malignant pattern did identify patients at significantly increased risk for recurrent teratoma-derived tumor. The authors conclude that cytologic atypia in the absence of invasion is not sufficient justification for altering the usual therapeutic strategies for patients with teratomatous metastases.     

Modified grading system for clinical outcome of intracranial non-germinomatous malignant germ cell tumors

This study investigated the clinical outcome of intracranial non-germinomatous malignant germ cell tumors (NGMGCTs). All histologically proven cases of NGMGCTs treated in Shanghai Huashan Hospital, Fudan University were reviewed. A total of 39 cases were analyzed. There were 15 mixed germ cell tumors, 15 immature teratomas, 7 embryonal carcinomas and 2 yolk sac tumors. Patients were treated surgically first, followed by radiotherapy and/or chemotherapy. Some patients also received gamma knife surgery. The common 5-year survival rate was 36.8%. According to Matsutani's grading system, the 5-year actuarial survival rate for patients in the intermediate and poor prognosis groups were 45.8 and 14.3%, respectively. Individual analysis of each type of tumor showed that the median survival time of embryonal carcinoma was 27 months, which is very close to that of the intermediate group (28 months). We therefore classified embryonal carcinoma into the intermediate group where the 5-year actuarial survival rate for patients in the new intermediate prognosis group was 42.6%. Further analysis of immature teratoma cases found that the 5-year survival rate of patients with immature teratoma who received gamma knife surgery is 100%. This rate exhibited a significant difference (P=0.0049) compared to that of patients who did not undergo gamma knife surgery. In conclusion, we consider surgery as the first choice of treatment although for different histologis, the type of the tumor should be treated separately.     

Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: a multiinstitutional retrospective analysis of 41 patients

BACKGROUND: The relative roles of surgical resection, radiotherapy, and chemotherapy in the management of patients with intracranial nongerminomatous malignant germ cell tumors have been controversial. The authors retrospectively investigated the results of different treatment regimens in patients with these tumors. METHODS: The records of 41 patients who were treated between 1981 and 2001 were reviewed. They were grouped into patients with a good prognosis (n=3), an intermediate prognosis (n=24), and a poor prognosis (n=14) based on the histology of their tumors. Fifteen patients (37%) underwent surgical resection and received radiotherapy, and 26 patients (63%) also received chemotherapy. The median follow-up of 18 patients who remained alive was 61 months (range, 14-194 months). RESULTS: The 5-year actuarial overall survival rates for patients in the good prognosis, intermediate prognosis, and poor prognosis groups were 100%, 68%, and 8%, respectively. In the analysis, histology alone had a statistically significant impact on overall survival (P<0.0001). All 3 patients in the good prognosis group were treated successfully with surgical resection and radiotherapy. In the intermediate prognosis group, the 5-year actuarial overall survival rate was 44% for patients who underwent surgical resection and received radiotherapy (n=9) and 84% for patients who also received chemotherapy (n=15; P=0.01). Patients in the poor prognosis group who underwent surgical resection and received radiotherapy (n=3) or who underwent incomplete resection and received both radiotherapy and chemotherapy (n=8) all died of disease, whereas 2 of 3 patients who underwent macroscopic total resection and received both radiotherapy and chemotherapy survived free of disease. CONCLUSIONS: The treatment of patients with intracranial nongerminomatous malignant germ cell tumors should be based on tumor histology. For patients who had a good prognosis (mature teratoma with germinoma), surgical resection and radiotherapy were sufficient; however, for patients in the intermediate prognosis group, multimodal treatment, including surgical resection, radiotherapy, and chemotherapy, was effective. Conversely, for patients in the poor prognosis group, more intensive multimodal treatment, including macroscopic total resection, may improve the survival rate.     

Treatment of recurrent germ cell tumors

Treatment of recurrent germ cell tumors is a complex undertaking. There are a number of clinical scenarios that can mimic relapse and, as such, a great deal of experience with management of germ cell tumors is required to recognize these rare but important situations that simulate recurrence. If recurrence is proven, standard chemotherapy with cisplatin, ifosfamide, and etoposide can result in approximately 30% of patients being long-term, disease-free survivors. Emerging technologies, e.g., high-dose chemotherapy and new drugs, may augment our current ability to salvage this patient population. Desperation surgery offers an additional opportunity for selected patients with localized chemotherapy-resistant relapse or those patients with late relapse of germ cell tumor.     

Teratoma with malignant transformation in germ cell tumors in men

Pathology reports of over 580 male patients with germ cell tumors treated between 1972 and 1982 were screened for teratomas in which malignant transformation was apparent. The diagnosis was established in 17 cases. The median age was 28 years (range, 14-52). For patients with disease limited to the testis, the median survival has not been reached, with all five patients surviving disease-free at 22+ to 120+ months. Among the 12 patients with metastatic disease, the median survival was 30.5 months (range, 12-69). All 12 patients were treated with cisplatin-containing regimens. Six had complete responses either to chemotherapy alone or to chemotherapy plus resection of residual disease. Four of the six complete responders relapsed, and three died of progressive disease. One patient with sarcomatous differentiation was treated with a doxorubicin-based regimen and had a partial remission, which lasted 8 months. Teratoma with malignant transformation, when found in metastatic sites, appeared to be a poor prognostic pathologic variant in male patients with germ cell tumors.