Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis.

Between 1977 and 1988, 67 patients underwent surgical removal of residual metastatic deposits following an aggressive chemotherapy regimen (cisplatin, vincristine, methotrexate and bleomycin alternating with etoposide, actinomycin D and cyclophosphamide) for disseminated germ cell tumours of the testis (stage IIB or above). Ninety-one surgical procedures were performed. There were 63 (69 per cent) retroperitoneal lymph node dissections, 16 (18 per cent) thoracotomies, three (3 per cent) hepatic resections, three (3 per cent) craniotomies, five (5 per cent) delayed orchidectomies and one anterolateral decompression of the vertebral column. Nine (13 per cent) patients required a repeat retroperitoneal node dissection and one patient needed a repeat thoracotomy to remove recurrent metastatic deposits during the period of follow-up. Multivisceral resections and vascular reconstruction procedures were required in 20 (30 per cent) patients undergoing retroperitoneal node dissection. Fifty-five (82 per cent) patients remain in complete remission with a mean follow-up period of 49.6 months (range 2-121 months). Nine (13 per cent) patients died with metastatic disease between 2 months to 4 years after operation. There were three deaths in the perioperative period (4 per cent). The histology of the resected metastases revealed undifferentiated active tumour in 20 (30 per cent) patients, differentiated mature teratoma in 29 (43 per cent) patients and fibrosis/necrosis in 18 (27 per cent) patients. Twelve (60 per cent) patients with undifferentiated elements and 15 patients (60 per cent) with raised preoperative tumour markers (poor prognostic categories) are in complete remission. Cytoreductive surgery in patients with metastatic germ cell tumours offers the best chance of remission following chemotherapy even in poor prognostic group categories.     

Bilateral germ cell tumours of the testis

Between 1952 and 1976, 760 men with testicular tumours were seen at The Royal Marsden Hospital. Of this group 21 (2.75%) developed tumours of the contralateral testis, in 2 instances synchronously and in the remaining 19 at intervals from 4 months to 15 years. Of 15 men in whom adequate history has been obtained, 7 (46%) had a history of maldescent and in all 7 patients the pathology of both tumours showed the same histological subtype. Only one example of malignant teratoma undifferentiated (MTU) as first tumour was encountered; 13 of 19 (68%) patients had seminomas and the second tumour was a seminoma in 11 patients (58%). Of the group of 21 patients, 12 (57%) are alive and disease-free. Of 14 Stage I patients (second tumour), 12 (85%) are considered cured of their 2 tumours. However, patients with evidence of extratesticular spread did badly, even if the second tumour was a seminoma, and treatment for these patients should include chemotherapy. Similarly, both Stage I MTU second tumours did badly.     

Sequential bilateral germ cell tumours of the testis

Bilateral germ cell tumours of the testis are rare but a rise in their incidence is expected since with the new therapeutic possibilities a significant improvement in prognosis has been achieved even in patients with advanced metastatic spread. Of the 210 patients treated for malignent germ cell tumours at our Department, six (2.9%) developed a contralateral testicular tumour. All patients had metachronous tumours and the second tumours occurred after an interval ranging between 1 and 22 years. The epidemiology, histology, diagnosis, therapy and prognosis are discussed, and the significance of regular self-examination of the remaining testis in patients with testicular tumour is emphasized.     

Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis

OBJECTIVE: To determine whether angiogenesis can be used as an additional prognostic indicator in patients with stage 1 germ cell tumours of the testis. PATIENTS AND METHODS: Paraffin sections were assessed immunohistochemically from 51 patients with clinical stage 1 germ cell tumours of the testis (28 seminoma, 23 teratoma) treated by orchidectomy and surveillance only. Sections were analysed for microvascular density (MVD), and expression of the angiogenic factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). In addition, in the seminoma cases the presence of mRNA for the lymphangiogenic factor VEGF-C was examined by in situ hybridization, and its corresponding receptor VEGFR-3 by immunohistochemistry. RESULTS: Teratoma specimens had a significantly higher mean (range) MVD (85, 26-163; P < 0.01) than both seminoma (37, 16-91) and four normal specimens (26, 18-30). Teratoma specimens also had significantly higher VEGF expression than both seminoma and normal specimens (P < 0.01). Despite these differences between groups, and indeed individual tumours, there was no significant correlation between MVD and VEGF, or between either MVD or VEGF and relapse-free survival. TP expression was significantly greater in tumours than in normal specimens (P < 0.02) but with very little inter-tumour variation. VEGF-C mRNA and VEGFR-3 protein were detected in a third to a half of cases, with expression mostly around endothelial vessels. CONCLUSIONS: The marked differences between normal testis and tumours implicate angiogenesis in the biology of germ cell tumours of the testis. In addition, the detection of factors involved in lymphangiogenesis in some seminomas, tumours which initially metastasize primarily to lymph nodes, indicate that although not prognostic in this study, further studies are warranted in both these areas in the search for further prognostic indicators and therapeutic targets.     

Postchemotherapy retroperitoneal lymph node dissection in advanced germ cell tumours of the testis

OBJECTIVES: To review the role of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in patients with advanced testicular germ cell tumours (TGCT) with special attention towards the indication, surgical technique, and oncological outcome. METHODS: A structured review of the literature until May 2007 using the PubMed database was performed. RESULTS: According to current guidelines and recommendations, PC-RPLND in advanced seminomas with residual tumours is indicated only if a PET scan performed 6-8 wk after chemotherapy is positive. In nonseminomatous TGCT, PC-RPLND is indicated for all residual radiographic lesions with negative or plateauing markers. Loss of antegrade ejaculation represents the most common long-term complication, which can be prevented by a nerve-sparing or modified template resection. The relapse rate after PC-RPLND is around 12%; however, it increases significantly to about 45% in cases with redo RPLND and late relapses. Patients with increasing markers should undergo salvage chemotherapy. Only select patients with elevated markers who are thought to be chemorefractory might undergo desperation PC-RPLND if all radiographically visible lesions are completely resectable. CONCLUSION: PC-RPLND represents a major part of the management of advanced TGCT undergoing inductive chemotherapy. Complete resection of all residual masses after primary chemotherapy results in a long-term disease-free survival of 95%. PC-RPLND requires a complex surgical approach and should be performed in experienced, tertiary referral centres only.     

Carcinoma-in-situ of the testis and invasive growth of different types of germ cell tumours. A revised germ cell theory

The hypothesis is proposed that seminomas and non-seminomas are histogenetically closely related and both types of germ cell tumours may originate from a common precursor cell: namely the germ cell showing the carcinoma-in-situ pattern. However, it is suggested that the spermatocytic seminoma is an exception as it may originate from spermatocytes.     

Experimental testicular germ cell tumorogenesis in mouse strains with and without spontaneous tumours differs from development of germ cell tumours of the adult human testis

The aim of this study was to undertake a morphological analysis of the earliest stages of experimentally induced (by genital ridge grafting) germ cell tumours in mouse strains with (129/Sv-ter) and without (MA) spontaneous tumorogenesis. Genital ridges from fetuses aged 12 or 13 days from 129/Sv-ter and MA were transplanted into the testes of adult 129/Sv-ter . The results show clearly that experimentally induced carcinoma-in-situ in mouse testes differs considerably from its human counterpart, found in patients with and without testicular germ cell tumours, and considered to be the precursor for all kinds of germ cell tumours of the adult testis apart from spermatocytic seminoma. The results indicate that development of testicular germ cell tumours is different in man and the mouse.     

Treatment of patients with poor prognosis anaplastic germ cell tumours (AGCT) of the testis and other sites

Between 1977 and 1986, 170 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovin), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979 we have been able to compensate for adverse prognostic factors. Since then each patient has received a minimum of three courses of POMB and 139 patients have completed therapy with an overall survival of 89%, and for those patients who had not received prior radiotherapy the survival is 92%. By increasing the number of courses of POMB, the initial serum concentrations of human chorionic gonadotrophin (hCG greater than 50,000 IU/I) and/or alpha-fetoprotein (AFP greater than 500 kU/l) have ceased to be poor prognostic variables. Neither stage at presentation nor the volume of metastatic disease is a major adverse prognostic variable using this chemotherapy.     

Current optimum management of anaplastic germ cell tumours of the testis and other sites

Between 1977 and 1985, 149 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovine), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979, we have been able to compensate for adverse prognostic factors. Since then each patient has received at least three courses of POMB and 118 patients have completed therapy. The overall survival rate since 1979 is 89% and for the 100 patients who had not received prior radiotherapy it is 92%. We established that an initial serum concentration of human chorionic gonadotrophin (HCG greater than 50,000 iu/l) and/or alphafetoprotein (AFP greater than 500 ku/l) indicated a poor prognosis. Between 1977 and 1979 the survival rate in 12 patients in this category was only 45%. After increasing the number of courses of POMB, the survival rate rose to 89% in 31 patients. However, patients who had received prior radiotherapy and who presented with high tumour markers (HCG greater than 50,000 iu/l and/or AFP greater than 500 ku/l) continue to have a poor survival rate (20% in five patients). With this chemotherapy, 14 of 16 patients (88%) presenting with liver metastases and 6 of 7 patients (86%) presenting with brain metastases are in complete remission. Neither the stage at presentation nor the volume of metastatic disease was a major adverse prognostic variable. We believe that POMB/ACE chemotherapy, followed by surgery in selected cases, is currently the best treatment for patients with AGCT.     

The changing presentation of germ cell tumours of the testis between 1983 and 2002

OBJECTIVE: To prospectively investigate the presentation of germ cell tumours (GCTs) of the testis in terms of stage or histology, as the incidence of this disease in increasing. PATIENTS AND METHODS: Patients diagnosed with GCT of the testis between 1983 and 2002 were categorised into three periods depending on the date of diagnosis of the GCT, and the presentational characteristics assessed. RESULTS There was a significant increase in the proportion of patients presenting with stage I disease (59% to 78%) and seminoma (43% to 58%) over this period. There was also a significant reduction in the size of the primary tumour (5 to 4 cm). CONCLUSION: A greater proportion of patients with GCT are presenting with stage I seminoma, the reasons for which are unclear, although earlier diagnosis through improved awareness of GCT may be important.     

Testicular germ cell tumours

Testicular germ cell tumours, owing to their variety in biological behaviour and morphological appearance, claim a place of their own in clinical oncology and tumour research. Much of the histogenesis has remained unexplained, as reflected by the different systems of pathological classification. This report sums up on basis of the literature, the current pathologic views on the question of testicular tumour genesis. Data obtained from immune histochemical examinations, animal experiments, ultrastructure studies, together with clinical observations, suggest that differentiation of the carcinomatous stem cells are apt to produce forms, transitional between seminomatous and non-seminomatous types of tumour. The possibility to set up a uniform, clinically appropriate nomenclature depends on the progress in histogenetic knowledge.     

Extragonadal germ cell tumours

In a retrospective study of patients treated for germ cell tumours, the authors found seven patients with primary extragonadal tumours in the retroperitoneum. These tumours are, in terms of histology, identical with germ cell tumours of the testis. The disease manifests itself by pain in the kidney region, palpable abdominal mass, weight loss, fever, and gynaecomasty. The diagnosis was confirmed histologically by examining tissue specimens obtained by probatory laparotomy and from the supraclavicular lymph nodes. The choice of therapy and prognosis of disease depend on the histological evidence. Orchiectomy is unnecessary provided both testes are clinically unaltered.     

Safety of surveillance in the management of stage I anaplastic germ cell tumours of the testis

A study was made of 46 patients with anaplastic germ cell tumours of the testis with no evidence of disease elsewhere as judged by computed tomography (CT) of thorax and abdomen, ultrasound and tumour marker measurements. A repeat CT 3 months after the first and clinical examination with chest X-ray and tumour marker measurements ensured that the 30.7% of patients who relapsed were detected promptly enough for them all to enter complete remission. Lymphography as part of the staging did not reduce the relapse rate. There was no difference between this group and a comparable group who underwent radiotherapy to para-aortic lymph nodes.     

Persistent carcinoma in situ of the testis after chemotherapy for advanced testicular germ cell tumours

The chemosensitivity of testicular carcinoma in situ (CIS) was analysed in 25 testes excised 10 weeks to 4.5 years following platinum-based chemotherapy. CIS was present in 8 of the 23 evaluable cases (35%), in 5 of which the lesion coexisted with invasive germ cell tumour. It is concluded that CIS may persist or recur after chemotherapy. This has implications for occult presentation of metastatic germ cell tumours and also for the management of the contralateral testis in patients with testicular germ cell tumours.     

The importance of prognostic factors in the individual treatment of patients with disseminated germ cell tumours

Following chemotherapy for disseminated testicular cancer, 55 patients underwent surgery because of residual tumour. The histological findings were viable tumour in 12 patients, mature teratoma in 12 and fibrosis and/or necrosis in 31. Retroperitoneal abdominal masses were evaluated radiographically before and after chemotherapy. The reduction in size of these masses after chemotherapy appeared to have prognostic significance. A decrease of more than 70% was always associated with fibrosis. A residual mass over 50 mm indicated viable tumour or mature teratoma. Seminoma or embryonal carcinoma was more likely to result in fibrosis/necrosis in the resected tissue. Both the Indiana and the EORTC classification models can be used for prognosis. Radiographic measurements before and after chemotherapy are of considerable prognostic significance. These objective indicators help in planning treatment and so diminish the side effects of therapy and maintain or even increase the high cure rate in disseminated testicular cancer.     

Chemotherapy of disseminated germ cell tumors

The fact that germ cell tumors can be successfully managed puts an extraordinary burden on the physician and health care system to ensure that the promise of cure is achieved in all patients except the small proportion that present with advanced refractory disease. Good risk disseminated disease should be treated with three cycles of bleomycin, etoposide and cisplatin (BEP) whereas those with more advanced disease should receive four cycles. Postchemotherapy resection of residual disease is commonly required. In patients in whom disease recurs after primary chemotherapy, salvage treatments can result in cure in 30–40% of patients. Physicians managing these patients should be aware of some of the pitfalls encountered when determining relapse and should be versed in the indications for salvage conventional dose chemotherapy, high dose chemotherapy, and the role of aggressive desperation surgery.     

Oncogenes and germ cell tumours

The central problem in cancer therapy is the poor selectivity of current systemic agents against the common solid tumours. The demonstration that unique segments of DNA, constant in location and conserved in evolution are involved in growth control opens new avenues for basic and clinical research. The function of the products of these genes needs to be elucidated. Examples of growth control functions include homology to growth factors, surface receptors, protein kinases and cell cycle control proteins. From DNA sequence data peptides predicted to be exposed within intact molecules can be constructed and used to produce monoclonal antibodies to oncogene products. Such antibodies have now been successfully used to demonstrate the intracellular localization of gene products as well as the cell cycle regulatory role of the c-myc protein. By having a battery of antibodies against the different gene products their direct clinical application for diagnosis and prognosis has become a reality. Immunohistology and flow cytometry permit the geographical and quantitative analysis of function in normal and neoplastic tissues. Furthermore, by purification and biochemical analysis the molecular basis for their action can be elucidated. It is likely that by the end of the decade new drugs that inhibit oncoprotein function will be available for clinical trial.     

The management of early stage non-seminomatous germ cell tumours of the testis: Edinburgh 1970-1981

This study describes the management of early stage non-seminomatous germ cell tumours of the testis in Edinburgh between 1970 and 1981. There were 69 patients in clinical Stage I and 22 patients in clinical Stage IIA. All were treated by orchiectomy and radiotherapy to the para-aortic nodes. Some of the patients with Stage IIA disease received additional therapy. The overall 5-year actuarial survival rate was 83%. In a group of 52 patients with Stage I disease who had had lymphography as part of their initial staging the 5-year actuarial survival rate was 94.2%. The overall relapse rate was 27/91 (29.7%). The relapse rate in State IIA disease was 11/22 (50%) and the 5-year actuarial survival rate was 64%. Patients with primary tumours beyond T1 had a significantly higher relapse rate than patients with T1 primary tumours: 10/20 (50%) and 13/52 (25%) respectively. The histology of the primary tumour did not have a statistically significant influence upon relapse rate.