Primary malignant mediastinal germ cell tumours: A literature review and a study of 18 cases

From 1957 to 1992, 18 cases of primary mediastinal germ cell tumours were referred to the Peter MacCallum Cancer Institute (PMCI). Six were seminomas, six were mixed germ cell tumours, two were embryonal cell carcinomas, three were teratocarcinomas and one was labelled an ‘anaplastic germ cell tumour’. Two of the 18 patients were female. For seminomas, surgical (and in one case chemotherapeutic) debulking, followed by radiotherapy produced the best results. Mediastinal doses ranged from 30 to 40 Gy. Local control was achieved in those patients receiving mediastinal radiotherapy. Four patients currently survive disease-free. The non-seminomatous germ cell tumours showed a significantly poorer survival, and only two of 12 patients remain alive in remission at 110 and 130 months after diagnosis. Survival has been updated as of November 1997. Attention is focused on the anterior position of the primary germ cell tumours in the mediastinum. A review of the literature up to and including 1997 is presented.     

Evaluation of AFP glycosylation heterogeneity in cancer patients with AFP-producing tumors

It has been postulated that analysis of alpha-fetoprotein (AFP) glycosylation heterogeneity in cancer patients whose AFP levels are elevated (e.g., non-seminomatous germ cell tumors, ovarian germ cell tumors and primary hepatocellular carcinoma) might provide useful clinical information. We undertook a study to determine whether scrutiny of AFP glycosylation heterogeneity in patients with non-seminomatous germ cell tumors would provide information useful in diagnosis, staging, prognosis, or monitoring for recurrence of disease following therapy. While an analysis of AFP glycosylation heterogeneity using Concanavalin A lectin chromatography did not provide useful information in regard to staging or prognosis, it does supply unique information useful in discriminating between benign liver dysfunction (e.g. alcoholic hepatitis, chemotherapy-related liver damage) and that due to nonsemininomatous germ cell tumors. It was also concluded that an analysis of Concanavalin A binding patterns is not sufficient to discriminate between recurrent non-seminomatous germ cell tumor and primary hepatocellular carcinoma in patients with elevated serum AFP.     

Etoposide, Cisplatin, Bleomycin, And Cyclophosphamide (Ecbc) As First-Line Chemotherapy for Poor-Risk Non-Seminomatous Germ Cell Tumors

Sixty-one patients with advanced metastatic non-seminomatous germ cell tumors were treated with etoposide 120 mg/m², cisplatin 30 mg/m², bleomycin 12 mg/m², and cyclophosphamide 300 mg/m² daily for four days; and additional bleomycin bolus injection of 15 mg was given on day 1. Fifty patients (82%) were treated with four to six courses at 3-week intervals. Forty patients (66%) attained complete remission, and further 7 patients (11%) achieved a marker-negative partial remission accounting for a favorable response rate of 77%). Hematologic toxicity was considerable and there were two treatment-related deaths. After a median observation time of 47 months (range 12 to 108 months), 43 patients were alive, of which 38 had continuous complete remission, one a second complete remission, two marker-negative stable disease and two progressive disease. Our results are similar to those reported by other investigators for poor-risk metastatic non-seminomatous germ cell tumors treated with dose-intensified regimens.     

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.     

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.     

The abnormal occurrence and the differentiation-dependent distribution of N-acetyl and N-glycolyl species of the ganglioside GM2 in human germ cell tumors. A study with specific monoclonal antibodies

Human primary germ cell tumors were analyzed for the presence of the ganglioside GM2 using three specific monoclonal antibodies which can distinguish the molecular species of the sialic acid moiety: the antibody MK1-16 is specific for N-acetyl GM2, MK2-34 is specific for N-glycolyl GM2, and MK1-17 detects both N-acetyl and N-glycolyl GM2. When the occurrence of the GM2 antigen was tested in 107 cases of human germ cell tumors by the immunohistochemical technique using these antibodies, seminoma was characterized as having the highest frequency of N-acetyl GM2 (89.4%, 42 of 47 cases) among germ cell tumors, followed by embryonal carcinoma (40.0%), and teratocarcinoma (26.6%). Compared with this, yolk sac tumors and choriocarcinoma had a much lower positive incidence of the N-acetyl GM2 antigen. On the other hand, the N-glycolyl GM2 antigen was not found at all in 47 cases of seminoma (0%), and the positive incidence was very low in embryonal carcinoma (6.6%), although considerably higher incidences were obtained with choriocarcinoma (25.0%), yolk sac tumor (22.2%), and teratocarcinoma (13.3%). The presence and molecular species of the GM2 antigens in these human germ cell tumors were also ascertained chemically by the thin-layer chromatography (TLC) immunostaining of the ganglioside fractions prepared from primary germ cell tumors. These results indicate that seminoma specifically contains N-acetyl GM2 and no N-glycolyl GM2, suggesting that N-acetyl GM2 could be a good marker for seminoma. On the other hand, non-seminomatous germ cell tumors were characterized by the presence of N-glycolyl GM2, one of the Hanganutziu-Deicher antigens (H-D antigens). Moreover, the positive occurrence of N-glycolyl GM2 correlated very well with the degree of differentiation of non-seminomatous germ cell tumors, i.e., the differentiated tumors such as yolk sac tumors, choriocarcinoma, and teratocarcinoma had a higher positive incidence of N-glycolyl GM2 type H-D antigen but a lower positive incidence of N-acetyl GM2 when compared with embryonal carcinoma, the most undifferentiated tumors among non-seminomatous germ cell tumors.     

Distribution of Testicular Tumors in Lebanon: A Single Institution Overview

Background: Testicular tumors constitute a rare type of cancer affecting adolescents and young adultswith recent reports confirming an increase in incidence worldwide. The purpose of this study was to estimatethe epidemiological characteristics and histological subtypes of testicular tumors in the Lebanese populationaccording to the WHO classification of testicular and paratesticular tumors. Materials and Methods: In thissingle institutional retrospective study, all patients diagnosed with a testicular tumor in Hotel-Dieu de FranceHospital University in Beirut between 1992 and 2014 were enrolled. The age, subtype based on the 2004 WHOclassification and body side of tumor were analyzed. Results: A total of two hundred and forty-four (244) patientsdiagnosed with a testicular tumor in our institution were included in the study. Two hundred and one patients(82.4% of all testicular tumors) had germ cell tumors (TGCT). Among TGCT, 50% were seminomatous tumors,48% non-seminomatous tumors (NST) and 2% were spermatocytic seminomas. The NST were further dividedinto mixed germ cell tumors (63.9%), embryonic carcinomas (18.6%), teratomas (15.4%) and yolk sac tumors(2.1%). The mean age for testicular tumors was 32 years. The mean age for germ cell tumors was 31 years andfurther subtypes such as seminomatous tumors had a mean age of 34 years, 28 years in non-seminomatous tumorsand 56 years in spermatocytic seminoma. Patients with right testicular tumor were the predominant group with55% of patients. Three patients (1.2%) presented with bilateral tumors. Conclusions: The distribution of differentsubgroups and the mean age for testicular tumors proved comparable to most countries of the world except forsome Asian countries. Germ cell tumors are the most common subtype of testicular tumors with seminomatoustumors being slightly more prevalent than non-seminomatous tumors in Lebanese patients.     

The first case of primary testicular germ cell tumor containing nephroblastoma as the only one non-germ cell component

Adult extrarenal nephroblastomas (Wilms' tumor) are extremely rare tumors. They show a higher incidence of non-seminomatous elements and these so-called 'teratoid' Wilms' tumors are suggested to be of germ cell origin. To date, however, the number of reported cases with gonadal teratoma containing nephroblastoma is very low, and due to this reason, there are no standardized criteria for the categorization and treatment of these lesions. To our knowledge, the first case of nephroblastoma arising in a non-atrophic testis has been reported and it is associated with a teratoma as morphologically identifiable germ cell tumor and rhabdomyosarcoma as a second non-germ cell element. We report the second case of an adult nephroblastoma that arose within the primary testicular teratoma in a non-atrophic testis. Teratoma and nephroblastoma within the same testis may have an important point to clarify the developmental mechanism in nephroblastomatous differentiation of germ cell tumors.     

Chemotherapy of extragonadal germ cell tumors

Forty-nine patients with histologically proven germ cell tumors arising in extragonadal sites were retrospectively reviewed. Included in the review were an additional seven patients with undifferentiated tumors with a pathologic appearance compatible with that of a germ cell tumor and elevated levels of serum biomarkers (beta subunit of human chorionic gonadotropin [beta-HCG] +/- alpha-fetoprotein [AFP]. Nineteen patients had a pure seminoma arising in an extragonadal site, whereas 30 patients had nonseminomatous germ cell tumors. Seven patients had primary undifferentiated tumors with elevated levels of serum biomarkers. Sixteen (84%) of the 19 patients with pure extragonadal seminomas with normal levels of serum AFP are alive and free of disease. Eighteen of these 19 patients received platinum-containing regimens and four had received prior chemotherapy that failed. Of the patients with nonseminomatous germ cell tumors, 12 (40%) of the 30 are alive and free of disease with vinblastine/bleomycin +/- cisplatin (13 patients) or CISCAII (cisplatin, cyclophosphamide, and doxorubicin) (nine patients) alternating CISCAII/VBIV (eight patients) chemotherapy. None of the seven patients with undifferentiated germ cell tumors are alive and free of disease. Three of the five patients with pure anterior mediastinal endodermal sinus tumors treated with chemotherapy remain alive and free of disease. Of the seven patients with choriocarcinomas arising in extragonadal sites, three are alive and free of disease. A classification for patients with extragonadal germ cell tumors incorporating site of origin, histology, and likelihood of being truly extragonadal is proposed. The implications of this classification are discussed.     

Successful management of metastatic and primary germ cell tumors in the brain

Nine men and one woman with brain metastases from nonseminomatous germ cell tumors have been treated between 1977 and 1984. All the men had lung metastases. Nine patients had elevated serum values of human chorionic gonadotrophin (HCG), the level was greater than 40,000 IU/l in seven. They were treated with sequential combination chemotherapy either POMB/ACE or EP/OMB in which the methotrexate was given at a dose of 1 g/m2 and intrathecal methotrexate was given during courses not containing intravenous methotrexate. Eight of ten patients are alive, off treatment with no evidence of active disease, of whom five have been in remission and off treatment for more than 18 months. Two patients with primary intracranial nonseminomatous germ cell tumors were treated in a similar fashion. One patient died from enlargement of differentiated teratoma; the other is alive 9+ months off treatment with no evidence of disease. These results, which are better than any previously reported, indicate that chemotherapy is the preferred treatment of primary or metastatic nonseminomatous germ cell tumors of the brain and that only rarely will these patients benefit from surgery or radiotherapy.     

Expression of HER-2/neu in testicular tumors

BACKGROUND: Although the overexpression of the Epidermal Growth Factor Receptor 2 (EGFR-2, HER-2/neu, c-erbB-2) in malignancies might predict chemoresistance and poor prognosis, its clinical relevance has not been widely studied and determined in testicular tumors. PATIENTS AND METHODS: Since teratomas are relatively chemoresistant tumors, we evaluated the HER-2/neu receptor status of 28 primary testicular tumors (7 pure teratomas, 21 mixed germ cell tumors containing teratomatous components) using a standardized immunohistochemical method (HercepTest Kit). RESULTS: Seven (25%) out of 28 non-seminomatous germ cell tumors showed HER-2/neu positivity. The teratomatous components of mixed GCTs showed HER-2/neu overexpression in 5 cases. Three of the 5 choriocarcinoma components of mixed tumors overexpressed HER-2/neu. In one case (teratoma + choriocarcinoma) both components showed HER-2/neu overexpression. No HER-2/neu overexpression was detected in other, less differentiated histological subtypes. Among the HER-2/neu-positive cases, 3 patients are in complete remission, 3 patients are in partial remission and one patient died after primary chemotherapy. CONCLUSION: Twenty-five percent of the non-seminomatous germ cell tumors which contain teratomatous components overexpress HER-2/neu protein. The overexpression is restricted to the more differentiated histotypes. Further molecular investigations and clinicopathological studies are necessary to determine the correlation between HER-2/neu overexpression and clinical resistance of testicular tumors.     

First-line chemotherapy of non-seminomatous germ cell tumors(NSGCTs)

Germ cell tumors (GCTs) account for the majority of testicular cancer cases occurring in men of young age and are divided into two main histologic groups, seminomas and non-seminomas. The introduction of cisplatin in the treatment of germ cell tumors was a breakthrough, classifying them among curable diseases. The identification of 3 subgroups of patients with non-seminomatous tumors (good-risk, intermediate and poor-risk), with different profiles concerning prognosis and response to treatment, supported clinical trials aiming to assess different treatment strategies and recommend the most effective and less toxic regimens. This review describes the toxic effects of therapy and the efforts aiming to overcome toxicity and improve treatment efficacy, focusing on the trials which form the basis of current standard treatment of non-seminomatous germ cell tumors.     

Hematologic disorders associated with primary mediastinal nonseminomatous germ cell tumors

BACKGROUND. The association between primary germ cell tumors of the mediastinum (the space between the lung pleura that contains the heart and other chest viscera) and hematologic malignancies has been described by retrospective analysis of patients treated at individual clinical centers. To better characterize the risk of hematologic disorders in patients with extragonadal germ cell tumors and to describe the clinical and biologic features of the disorders, we studied an unselected population in a large, international, multicenter database. METHODS. Six hundred thirty-five patients treated at 11 centers in the United States and Europe from 1975 through 1996 were evaluated retrospectively. RESULTS. A hematologic disorder was observed in 17 patients with germ cell tumors. All cases developed among the 287 patients with primary mediastinal nonseminomatous germ cell tumors, giving an incidence rate in this group of 2.0% (95% confidence interval [CI] = 1.1%-3.1%) per year over a median follow-up time of 3 years. The risk of developing hematologic disorders was statistically significantly increased in patients with primary mediastinal nonseminomatous germ cell tumors in comparison with the age-matched general population (standardized incidence ratio = 250; 95% CI = 140-405). The median time to onset of hematologic neoplasia was 6 months (range, 0-47 months), and the median survival after diagnosis of the hematologic disorder was 5 months (range, 0-16 months) (two-sided P<.0001, comparing survival from the time of diagnosis of the germ cell tumor of patients with and without hematologic disorders). CONCLUSION. In our study, approximately one in 17 patients with primary mediastinal nonseminomatous germ cell tumors was affected by a hematologic disorder, whereas no cases were seen among 334 patients with other extragonadal germ cell tumors. The hematologic disorder had a statistically significant impact on prognosis, with none of the 17 reported patients surviving for more than 2 years.     

Extraskeletal osteosarcoma. A clinicopathologic review of 26 cases

The clinical records and histopathologic features in 26 cases of extraskeletal osteosarcoma (ESOS) diagnosed at M.D. Anderson Cancer Center (Houston) between 1950 and 1987 were reviewed. Presentation was usually that of an enlarging soft tissue mass. The thigh (11 cases), upper extremity/shoulder girdle (three cases), and retroperitoneum (three cases) were the most common anatomic sites. Tumor size ranged from 2.5 to 30 cm. The predominant histologic pattern was osteoblastic in four cases, chondroblastic in two, fibroblastic or pleomorphic malignant fibrous histiocytoma (MFH)-like in four, giant cell type MFH-like in one, and small cell in one. Various mixtures of these patterns were seen in the remaining 14 tumors. The telangiectatic pattern was not seen as the predominant component in any primary tumor but was observed as a minor component. Thirteen tumors recurred locally and 16 metastasized; five patients had distant metastases at presentation. The lungs, bone, and soft tissue were the most frequent metastatic sites. Sixteen patients died of disease at 2 to 54 months, one patient died of unrelated causes at 61 months, seven patients were alive with no evidence of disease (NED) at 30 to 122 months, and two patients were alive with disease at 28 and 54 months, respectively. Tumor size (less than 5 cm versus greater than or equal to 5 cm) was the main prognostic factor; all patients alive with NED for whom accurate tumor measurements were available (six of seven) had neoplasms measuring less than 5 cm that were amenable to complete surgical excision. Histologic pattern and other clinicopathologic features did not significantly affect outcome.     

Primary mediastinal germ cell tumors. Histologic patterns of treatment failures at autopsy

Twenty-five patients presented with primary mediastinal germ cell tumors at Roswell Park Memorial Institute between 1959 and 1984. All patients were treated by surgery and chemotherapy with or without radiotherapy. Four patients are still alive, and 21 patients died of mediastinal germ cell tumor and its sequelae. Two patients were found to have testicular scars and were dropped from the study. Nongerm cell malignant transformation of a teratoma occurred in five of the remaining 17 patients (29%), resulting in three adenocarcinomas and two sarcomas. Another patient developed leukemia. Metastatic disease most commonly involved the lungs, mediastinal lymph nodes, liver, bone, retroperitoneum, and heart. Respiratory failure was the cause of death in 12 patients. Of the possible mechanisms of germ cell transformation into malignant nongerm cell tumors discussed, this study suggests that chemotherapy alone is unlikely to induce stem cell differentiation. The presence of mature, differentiated teratoma within the primary lesion may be indicative of a poorer prognosis.     

Malignant mixed germ-cell-sex cord-stromal tumors of the ovary associated with isosexual precocious puberty

Two cases of hormonally active, metastasizing malignant mixed germ cell-sex cord-stromal tumors are described in otherwise normal prepubertal girls. Isosexual precocity was noted 5 months and 1 month before surgery. One child died 1 year after presentation, and the other was alive, with no apparent tumor, 1 year after diagnosis. These two cases represent the first recorded instance of a unique tumor in which metastases of several cell types were encountered.     

Sequential combination chemotherapy for malignant germ cell tumors of the ovary

Fourteen patients with malignant ovarian germ cell tumors were treated postoperatively with a short-term, sequential regimen combining cisplatin, vincristine, methotrexate, bleomycin, dactinomycin, cyclophosphamide, etoposide, Adriamycin (Adria Laboratories, Columbus, OH), and vinblastine (POMB/ACE/PAV). Two patients had Stage I disease, Five had Stage II, five had Stage III, and two had Stage IV. The histologic diagnosis was immature teratoma in five cases (two cases were Grade 2 and three cases were Grade 3) endodermal sinus tumor in two cases, dysgerminoma in three cases, and mixed germ cell tumors in four cases. The chemotherapy regimen appeared to be highly effective against all histologic types, including advanced stages, with 12 of 14 (86%) overall sustained remissions. The median duration of treatment was 5 months. The toxicity of the regimen, which contained low total doses of cisplatin and bleomycin, was only moderate. After a median follow-up of 53+ months, 13 patients were alive without evidence of disease. The results and toxicity obtained were compared with those from other currently used regimens. Also, some comments on initial surgery and second-look surgery are given.     

Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis.

PURPOSE: To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies. PATIENTS AND METHODS: Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology. RESULTS: After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P =.0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy. CONCLUSION: Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.     

Wait-and-see policy in clinical stage I non-seminomatous germ cell tumors of the testis

Thirty-three patients with a non-seminomatous germ cell tumor of the testis in clinical stage I were treated only by orchidectomy. The very careful follow-up--with tumor marker assays every 3 weeks, chest X-rays every 6 weeks and CT-scans of the lungs and retroperitoneum every 3 months--revealed metastases in 7 of the patients (21%). All these relapses were diagnosed within 6 months of the orchidectomy. Para-aortic node metastases were found in 5 of the 7 patients, with additional inguinal node metastases in 1 and additional lung metastases in 1; 2 patients had only lung metastases. Six of the 7 patients with a relapse were given chemotherapy (PVB); 1 patient refused chemotherapy. In view of residual disease a surgical excision was performed; it revealed necrosis as well as mature teratoma. All 33 patients are still alive, the post-orchidectomy follow-up period being 12-38 months.     

Study of total serum amylase, its salivary and pancreatic fraction and the pancreatic to salivary amylase ratio in testicular tumours.

Serum levels of total amylase, its pancreatic fraction (P), salivary fraction (S), and the ratio of pancreatic to salivary fraction (P/S) were determined in 52 cases of histologically proved testicular germ cell tumours and 33 healthy controls. Total serum amylase remained unchanged, but the salivary fraction had a lower mean value. P/S ratio and the pancreatic fraction were significantly elevated in both seminomatous and non- seminomatous tumours. The ratio was more frequently raised in non-seminomatous (100%) as compared to seminomatous (66.67%) tumors. Following treatment there was no appreciable fall in P/S ratio in non-seminomatous tumors whereas in seminomas there was a slight increase in the ratio. The pancreatic fraction showed a transient fall in seminomatous but not in non-seminomatous tumors following treatment. The pancreatic fraction of amylase and the P/S ratio may help in the diagnosis of testicular germ cell tumor but does not appear to be of use in assessment of prognosis or monitoring the course of the disease during treatment.