Occurrence of malignant non-germ cell components in primary mediastinal germ cell tumours.

METHODS: Thirty-five patients with primary mediastinal germ cell tumours (PMGCT) underwent primary thoracotomy in a 30-year period (1965-1994). Of the 35 patients, 12 had benign teratomas, five pure seminomas and 18 non-seminomatous germ cell tumours. RESULTS: Out of 18 non-seminomatous germ cell tumours, 14 comprised more than one malignant component. In two cases malignant teratomas had an additional malignant non-germ cell component: one a mixed sarcomatous component and the other a neuroendocrinal component. There were different methods of treatment between 1965 and 1994. All but one of patients with seminomas survived for 5 years. Among 18 patients with malignant PMGCT, all but two died within 5 years (mean survival rate was 15 months). CONCLUSIONS: When planning treatment of patients with malignant PMGCT we have to take into account the fact that malignant non-germ-cell components may occur. In this circumstances, surgical resection after initial chemotherapy is recommended.     

原发纵隔恶性生殖细胞瘤32例临床分析

目的:探讨纵隔恶性生殖细胞瘤(malignant germ cell tumors,MGCT)的临床特点、治疗和预后。方法:32例纵隔MGCT患者,精原细胞瘤18例,非精原细胞瘤14例。所有患者均采用手术和(或)放疗和(或)化疗等多学科综合治疗的方法。结果:非精原细胞瘤患者中位生存期(OS)32.4个月,中位无进展生存期(PFS)18个月,5年无复发生存率和总生存率均为28.6%。精原细胞瘤患者5年无复发生存率和总生存率分别为83.3%和85.6%,中位OS和PFS均未到达。精原细胞瘤患者OS和PFS均明显好于非精原细胞瘤患者,P值分别为0.001 4和0.000 7。结论:纵隔精原细胞瘤采用多学科综合治疗方法能取得较好的治疗效果,本研究的结果与文献报道相符。纵隔非精原细胞瘤的治疗效果有待进一步提高。非精原细胞瘤是影响纵隔恶性生殖细胞瘤预后的重要因素。     

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。     

Frequent PD-L1 expression in testicular germ cell tumors

Background:

Many testicular germ cell cancers are curable despite metastatic disease, but about 10–15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies.

Methods:

Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue.

Results:

Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells.

Conclusions:

This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.     

Treatment of men with metastatic non-seminomatous germ cell tumours with cyclical POMB/ACE chemotherapy

Background: An alternating combination chemotherapy schedule for advancednonseminomatous germ cell tumours (NSGCT) has been in use since 1977.Patients and methods: Three hundred thirty-nine men with metastatic NSGCTwere treated with POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin,actinomycin D, cyclophosphamide and etoposide), including 42 who had receivedprevious chemotherapy or radiotherapy. Previously untreated patients wereclassified according to the International Germ Cell Cancer Collaborative Group(IGCCCG) model, and 31% were in the worst prognostic group.Results: The median follow-up is eight years. The overall survival at fiveyears is 82% (95% confidence interval (CI);78%–85%). The survival of untreated patients exceeded thatfor previously treated patients (log-rank P = 0.04) and of testicular tumoursexceeded that for primary extragonadal tumours (log-rank P < 0.0001). Thesurvival of men with IGCCCG poor prognosis disease at three years is75% (95% CI: 65%–84%) compared to 50%in the large cohort which was used to derive the model. There were five earlytreatment related deaths. In addition, five patients developed acuteleukaemia, one developed a second primary lung adenocarcinoma, one man diedof pulmonary fibrosis and three men died of cerebrovascular or cardiovasculardisease.Conclusions: The POMB/ACE schedule has been employed in a large series ofmen with metastatic NSGCT over two decades. The fatal toxicity is equivalentto that described for simpler regimens. It yields equivalent response ratesand survival in men with good prognosis disease and appears to achieve bettersurvival in patients with poor prognosis disease.     

DNA topoisomerase I and II expression in drug resistant germ cell tumours

A small number of testicular germ cell tumours are refractory to current chemotherapy regimens. DNA topoisomerase I is the target for several new drugs and a potential candidate treatment for chemorefractory germ cell tumours. DNA topoisomerase II alpha is the target for etoposide, which is currently used regularly in germ cell tumour treatment. The expression of DNA topoisomerase I and II alpha were therefore assessed immunohistochemically in a range of testicular tumours, especially those with persistent malignant elements on retroperitoneal lymph node dissection. Pre-chemotherapy orchidectomy specimens were matched with post-chemotherapy retroperitoneal lymph node dissections to examine changes in expression. There was considerable variation in the expression of topoisomerase I in different tumour types. Both yolk sac tumours and teratoma, mature showed universal expression of topoisomerase I, while 38% of seminomas and 30% of embryonal carcinomas were positive. Strong topoisomerase II alpha expression was found in embryonal carcinoma. There was a negative correlation between topoisomerase I and II alpha expression (P=0.004) and downregulation of topoisomerase II alpha after chemotherapy (P=0.02). Topoisomerase I expression appears to increase in those cases with residual teratoma, mature, but is largely unchanged in those cases remaining as embryonal carcinoma. These results suggest that topoisomerase I inhibitors may be useful in chemorefractory germ cell tumours, especially yolk sac tumours and where there are unresectable residual teratoma, mature deposits.     

原发性纵隔恶性生殖细胞肿瘤临床和预后分析

目的探讨原发性纵隔恶性生殖细胞肿瘤(PMGCT)的临床病理特点、治疗方法和预后因素。方法回顾性分析29例PMGCT患者的临床资料。结果29例患者均为男性,平均发病年龄26.1岁,肿瘤均来源于前纵隔,平均最大径16.0 cm。其中原发性纵隔精原细胞瘤(PMSGCT)5例(17.2%),原发性纵隔非精原细胞瘤(PMNSGCT)24例(82.8%)。PMGCT最常见症状是憋气、咳嗽与胸痛,其治疗采用化疗、手术、放疗相结合的综合治疗模式。PMNSGCT组中化生存期为19.0个月, 1年和2年生存率分别为65.3%和28.1%。PMSGCT组均长期生存,预后优于PMNSGCT组(P= 0.008)。多因素分析结果显示,病变局限于纵隔、以顺铂为基础的联合化疗是PMNSGCT患者预后的独立影响因素。结论PMGCT以PMNSGCT为主,主要治疗手段是以顺铂为基础的联合化疗。PMNSGCT预后明显差于PMSGCT,并与病变范围、化疗与否相关。     

Platinum-based chemotherapy of primary extragonadal germ cell tumours: the Hellenic Cooperative Oncology Group experience.

Extragonadal germ cell tumours (EGCT) are uncommon, most frequently arise in the mediastinum and retroperitoneum and have variable responses to platinum-based chemotherapy. A retrospective analysis was performed on 38 patients with EGCT treated with cisplatin-based (CDDP) or carboplatin-based (CBDCA) chemotherapy between 1984 and 1998. Twenty-four patients had nonseminomatous germ cell tumours (NSGCT) and 14 seminoma. Twenty-two tumours arose in the mediastinum (13 nonseminomas, 9 seminomas) and 16 in the retroperitoneum (11 NSGCT, 5 seminomas). Initial surgery included complete resection in 1 patient, biopsy in 27 patients and debulking surgery in 10 patients. Complete response rates with chemotherapy +/- surgery were as follows: mediastinum 14 of 21 (66.66%) patients (8 of 12-75% NSGCT, 6 of 9-66.66% seminomas) and retroperitoneum 14 of 16 (87.5%) patients (9 of 11-81.81% NSGCT, 5 of 5-100% seminomas). One patient who underwent complete resection of a mediastinal malignant teratoma combined, received PVB chemotherapy on an adjuvant basis and remains alive and disease-free. Three additional seminoma patients who achieved partial response after chemotherapy remain alive and disease-free following mediastinal radiotherapy. All 14 patients with extragonadal seminomas remain alive with no evidence of disease at a median follow-up of 49 months (range 7-164), giving an overall survival of 100%. Nine of 13 (69.23%) patients with mediastinal NSGCT are long-term disease-free at a median follow-up of 43.5 months (range 7-152). Nine of 11 (81.81%) patients with retroperitoneal NSGCT remain alive and disease-free at a median follow-up of 56 months (range 14-110). Complete surgical resection of residual mass was undertaken in 10 patients (3 seminomas, 7 nonseminomas). The histology revealed necrosis/fibrosis in 6 patients (3 seminomas, 3 NSGCT) and viable cancer in 4 patients. Patients who had viable malignant cells in the resected specimens received two more courses of VelP chemotherapy. None of our patients had relapsed at the time of this analysis. None of our 6 patients who underwent testicular biopsy (1 patient) or orchiectomy (5 patients) due to suspicious ultrasound of the testis were found to have testicular tumour or fibrotic scar. In conclusion, this retrospective analysis showed significant responses in patients with either mediastinal or retroperitoneal NSGCT treated with CDDP- or CBDCA-based chemotherapy +/- surgery. All patients with extragonadal seminomas remain alive with no evidence of disease, regardless of the site at presentation.     

Primary malignant mediastinal germ cell tumors: a study of eleven cases and a review of the literature

From 1957 to 1988 eleven cases of primary mediastinal germ cell tumor were referred to the Peter MacCallum Cancer Institute (PMCI). Four were seminomas, three were mixed germ cell tumors, two were embryonal carcinomas and two were teratocarcinomas. Two of the eleven patients were female. For seminoma, surgical debulking and post-operative irradiation produced the best results. Mediastinal doses ranged from 30 to 37.5 Gy. Local control was achieved in all cases; two patients survive disease-free. The non-seminomatous germ cell tumors showed a significantly poorer survival with only one of seven patients remaining alive in remission at 15 months. One other case of non-seminomatous tumor remains alive but in relapse at 23 months. Attention is focused on the anterior position of primary germ cell tumors in the mediastinum. A review of the literature is presented.     

Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery.

A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free.     

纵隔生殖细胞瘤临床分析

目的:分析生殖器外纵隔生殖细胞瘤诊断和影响预后的因素。方法:65例纵隔生殖细胞瘤均行开胸手术治疗。单纯完全摘除肿瘤59例;姑息性切除1例;肿瘤摘除联合肺叶切除或胸膜纤维板剥脱术3例;开胸探查2例。恶性生殖细胞瘤术后均行辅助放、化疗。结果:良性畸胎类肿瘤手术摘除或合并肺、胸膜切除后效果良好。恶性生殖细胞瘤,尤其是精原细胞瘤切除后,辅助放、化疗仍可获得较好的远期生存。3年生存率66.7%。结论:纵隔生殖细胞瘤是常见的纵隔肿瘤,诊断后积极手术治疗可获得较好的结果。     

Genomic copy number and expression patterns in testicular germ cell tumours

Testicular germ cell tumours of adults and adolescents (TGCT) include seminomas (SE) and nonseminomas (NS), with spermatocytic seminomas (SSE) representing a distinct entity in older men. SE and NS have gain of 12p material in all cases, whereas SSE are associated with overrepresentation of chromosome 9. Here, we compare at the chromosomal level, copy number imbalances with global expression changes, identified by comparative expressed sequence hybridisation analyses, in seven SE, one combined tumour, seven NS and seven cell lines. Positive correlations were found consistent with copy number as a main driver of expression change, despite reported differences in methylation status in SE and NS. Analysis of chromosomal copy number and expression data could not distinguish between SE and NS, in-keeping with a similar genetic pathogenesis. However, increased expression from 4q22, 5q23.2 and 9p21 distinguished SSE from SE and NS and decreased copy number and expression from 2q36-q37 and 6q24 was a specific feature of NS-derived cell lines. Our analysis also highlights 19 regions with both copy number and expression imbalances in greater than 40% of cases. Mining available expression array data identified genes from these regions as candidates for involvement in TGCT development. Supplementary data is available at http://www.crukdmf.icr.ac.uk/array/array.html.     

First-line sequential high-dose VIP chemotherapy with autologous transplantation for patients with primary mediastinal nonseminomatous germ cell tumours: a prospective trial

To determine the efficacy of first-line sequential high-dose VIP chemotherapy (HD-VIP) in patients with primary mediastinal nonseminomatous germ cell tumours (GCT), 28 patients were enrolled on a German multicentre trial. High-Dose VIP chemotherapy consisted of 3-4 cycles of dose-intensive etoposide and ifosfamide plus cisplatin, q22days, each cycle followed by autologous peripheral blood stem cell transplantation plus granulocyte-colony stimulating factor (G-CSF) support. One cycle of standard-dose VIP was applied to harvest peripheral blood stem cells. Ten patients had mediastinal involvement as the only manifestation (36 %), 18 of 28 patients had additional metastatic sites, such as lung (n=17; 61%), liver (n=7; 25%), bone (n=5; 18%), lymph nodes (n=3; 11%) and CNS (n=3; 11%). Median follow-up was 43 months (range, 7-113) for all patients and 52 months (range, 22-113) for surviving patients. Nineteen of 28 patients obtained a disease-free status; 11 with HD-VIP alone and eight with adjunctive surgery. In addition, one of the four patients with marker negative partial remission after HD-VIP without resection of residual masses is currently alive. Two patients developed recurrence of GCT or teratoma. Two patients have died due to an associated haematologic disorder. The 2-year progression-free survival and overall survival rates are 64 and 68%, respectively. This report represents a subgroup analysis of 28 patients with mediastinal nonsemina within the German first-line study for 'poor prognosis' GCT. Compared to data of an international database analysis including 253 patients with mediastinal nonseminoma treated with conventional chemotherapy, the results may indicate that HD-VIP results in an approximately 15% survival improvement.     

26例原发性纵隔恶性生殖细胞瘤的诊治

目的:探讨原发性纵隔恶性生殖细胞瘤的诊治及外科手术的作用.方法:对26例收治的原发性纵隔恶性生殖细胞瘤的临床资料进行回顾性分析.结果:22例手术治疗患者中,11例根治性切除,10例姑息性切除,1例探查,手术并发症发生率及死亡率分别为18.2%和9.1%,其中12例术后给予以顺铂为主的联合化疗,4例予以放疗.手术治疗患者术后病理为无性生殖细胞瘤12例,精原细胞瘤5例,未成熟畸胎瘤5例.3例未成熟畸胎瘤及1例胚胎癌患者明确诊断后未手术而给予放疗或放、化疗.本组26例患者中仅2例精原细胞瘤生存满5年,17例已证实死亡,除2例手术死亡外均死于肿瘤复发转移.结论:原发性纵隔恶性生殖细胞瘤的治疗应强调以化疗为主的综合治疗,外科切除只宜做为阶段性的辅助手段,手术时机把握应以具体患者情况而定.     

Successful management of brain metastasis from malignant germ cell tumours with standard induction chemotherapy

Because of possible long-term toxicity, cranial radiotherapy (RT) was withheld as part of standard treatment for brain metastasis (BM) from non-seminomatous germ cell tumours (NSGCT). This study evaluates this change in management in our institute. Twenty-two consecutive patients with BM from NSGCT were analysed. Ten patients presented with BM at initial diagnosis (group 1), two patients developed BM at extra-cranial complete remission (CR) (group 2), and ten patients during treatment of the primary tumour without achieving CR (group 3). All patients received cisplatin-based induction chemotherapy. In group 1, three patients with a single metastasis and three patients with multiple BM underwent craniotomy. Five patients received chemotherapy and whole brain RT (WBRT), and five patients received chemotherapy without WBRT. In group 2, both patients underwent craniotomy for a relapse with multiple BM. One patient received additional high-dose (HD) chemotherapy with WBRT, and the other HD chemotherapy without WBRT. In group 3, one patient underwent craniotomy, seven patients received WBRT, and four patients additional HD chemotherapy. In group 1, five of ten patients (50%) achieved CR (follow-up 49–245 months), in four of those five without WBRT. In group 2, both patients achieved CR (follow-up 146 and 211 months). In group 3, one of ten patients (10%) achieved CR after HD chemotherapy and WBRT (follow-up 107 months). It is concluded that cure in patients with BM from NSGCT can be achieved with standard induction chemotherapy without WBRT.     

Somatic mutations of KIT in familial testicular germ cell tumours

Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.     

Primary Mediastinal Germ Cell Tumors—The University of Western Ontario Experience

Extragonadal germ cell tumors account for 2–5.7% of germ cell tumors (GCTs). Of these, primary mediastinal GCTs (PMGCTs) are responsible for 16–36% of cases. Given the rarity of these tumors, specific treatment strategies have not been well defined. We report our experience in treating these complex patients. In total, 318 men treated at our institution with chemotherapy for GCTs between 1980 and 2016 were reviewed. PMGCT was defined as clinically diagnosed mediastinal GCT with no evidence of testicular GCT (physical exam/ultrasound). We identified nine patients diagnosed with PMGCT. All patients presented with an anterior mediastinal mass and no gonadal lesion; four patients also had metastatic disease. Median age at diagnosis was 30 years (range, 14–56) and median mass size at diagnosis was 9 cm (range, 3.4–19). Eight patients had non-seminoma and one had pure seminoma. All patients received cisplatin-based chemotherapy initially. Surgical resection was performed in four patients; three patients had a complete resection and one patient was found to have an unresectable tumor. At a median follow-up of 2 years (range, 3 months–28 years) six patients had progressed. Progression-free survival was short with a median of 4.1 months from diagnosis (range 1.5–122.2 months). Five patients died at a median of 4.4 months from diagnosis. One and 5-year overall survivals were 50% and 38%, respectively. PMGCT are rare and aggressive. Our real-life Canadian experience is consistent with current literature suggesting that non-seminoma PMGCT has a poor prognosis despite prompt cisplatin-based chemotherapy followed by aggressive thoracic surgery.     

Malignant Hematologic Disorders Arising from Mediastinal Germ Cell Tumors. A Review of Clinical and Biologic Features

Since 1985, the biological association of mediastinal germ cell tumors and certain hematologic malignancies has been recognized. Continued investigation of such patients and new cytogenetic information brings additional insights into the clinical aspects of this syndrome as well as hinting at the possible etiology. This syndrome only occurs in patients with non-seminomatous germ cell tumors arising within the mediastinum. The interval from the diagnosis of the germ cell tumor to the development of the hematologic malignancy is brief (usually less than 6 months). Careful characterization of the hematologic malignancies in this patient population suggests a predominance of abnormalities within the megakaryocytic lineage. Recent cytogenetic analysis in one patient identified the most common abnormality of germ cell cancers, isochromosome 12p, in the mediastinal germ cell tumor as well as in the subsequent leukemic blasts. i12p is not a cytogenetic abnormality associated with the development of leukemia. The clinical evidence as well as this new cytogenetic information suggest strongly that the two abnormalities are clonally related and that the hematologic malignancy may arise as a consequence of defferentiation of the multipotent malignant germ cell.     

44例儿童青少年恶性生殖细胞肿瘤综合治疗结果分析

背景与目的:目前儿童青少年恶性生殖细胞瘤采用综合治疗,总生存率已达75%以上,然而,不同分期、病理类型和发病部位的患者有不同的预后。本文分析儿童青少年恶性生殖细胞瘤的临床特点、综合治疗的效果和影响预后的因素,并探讨其治疗策略。方法:对1997年1月～2005年12月中山大学肿瘤防治中心收治的儿童青少年恶性生殖系统肿瘤患者的临床表现、综合治疗疗效和不良预后因素进行分析;采用Kaplan-Meier法计算全组生存率。结果:44例患者中,25例行术后辅助化疗;1例单纯手术;18例行诱导化疗,其中7例患者化疗后肿瘤缩小行手术切除,2例原发纵隔绒癌伴多发转移患者化疗后行残留病灶放疗,1例术后腹腔转移和1例术后肺转移患者化疗后获得完全缓解,1例原发纵隔内胚窦瘤化疗后部分缓解,未做进一步治疗,6例患者化疗无效进展死亡。化疗的患者均采用含铂类化疗方案治疗2～7个疗程。中位随访时间32个月,全组3年总生存率为84.8%;Ⅰ Ⅱ期患者3年生存率为100%,Ⅲ期为83.3%,Ⅳ期为65.6%,复发患者为66.7%;初治生殖器内(睾丸和卵巢)肿瘤患者3年生存率为96.0%,生殖器以外肿瘤患者为61.0%。结论:手术联合含铂类药物化疗能明显改善儿童青少年生殖细胞瘤的疗效和生存率,但对Ⅳ期、复发转移和生殖器以外的生殖细胞瘤患者应探讨新的方案和增加剂量强度。