Germ Cell Tumors Of Testis Research Articles

Long-term results after inferior vena caval resection during retroperitoneal lymphadenectomy for metastatic germ cell cancer

Purpose: The long-term sequelae of inferior vena caval (IVC) resection during retroperitoneal lymph node dissection for metastatic nonseminomatous germ cell testis tumor (NSGCT) were assessed. Methods: Between December 1973 and September 1996, 2126 of our patients underwent RPLND for retroperitoneal nodal metastases from NSGCT; 955 had bulky disease (stages B2, B3, or C) after cytoreduction chemotherapy. Of this latter group, 65 patients (6.8%) required infrarenal IVC resection during tumor excision for cure. Our protocol does not include IVC reconstruction in such cases. Indications for IVC resection included tumor encasement or encroachment, postchemotherapy desmoplastic compression, or thrombus with tumor or clot in which cavotomy and thrombectomy cannot be performed. Results: Twenty-four of the 65 patients (postoperative follow-up period range, 11 months to 16 years; median, 89 months) were alive and able to be examined or interviewed by written and/or phone survey to assess the long-term morbidity of their IVC resection. Based on the 1994 American Venous Forum International Consensus Committee reporting standards, the clinical classifications of these 24 patients were C 0A (4), C 3S (4), C 4A (2), C 4S (13), and C 6A (1). Long-term disability was mild or absent in 75% of these patients. Conclusion: Only 1 (4.2%) of the patients surveyed had chronic venous sequelae that would fulfill the accepted criteria for subsequent elective IVC reconstruction. Despite recent reports of IVC reconstruction demonstrating relatively good patency rates and low morbidity, the addition of such a complex, time-consuming procedure to extensive retroperitoneal lymph node dissection for metastatic NSGCT involving IVC resection is generally not necessary. (J Vasc Surg 1998;28:808-14.)

LAPAROSCOPIC RETROPERITONEAL LYMPHADENECTOMY FOR CANCER OF THE TESTIS

Laparoscopic retroperitoneal lymph node dissection (RPLND) is a technically advanced procedure that has been undertaken for the management of low-stage nonseminomatous germ cell testis tumor. Although it has been shown to be an effective staging technique, its role as a therapeutic operation is currently unknown. Laparoscopic RPLND requires longer operative times but offers the patient all the advantages of minimally invasive surgery, such as less postoperative pain and shorter hospitalization and convalescence. The role of laparoscopic RPLND for the evaluation of residual abdominal masses following chemotherapy is currently being examined.

SURVEILLANCE FOR STAGE I TESTICULAR SEMINOMA: Is It A Good Option?

Postorchidectomy treatment options in patients with stage I seminoma include surveillance (reserving treatment for patients who relapse), adjuvant radiation therapy (RT), and adjuvant chemotherapy. Adjuvant retroperitoneal RT remains the treatment of choice in most centers; however, the success of surveillance in stage I nonseminomatous germ cell testis tumors, the establishment of curative chemotherapy for advanced disease, and the improvements in CT have led to re-examination of the standard treatment approach. The available data from the surveillance and adjuvant RT series suggest that almost 100% of patients with stage I testicular seminoma are cured, whichever approach is chosen. This article presents an overview of the available information on all treatment options, the pros and cons of each approach, and indications for where surveillance fits into the armamentarium of clinicians dealing with this disease.

The Stage i Yolk SAC Tumor of Testis in Children Younger than 2 Years, Chemotherapy or not?

Yolk sac tumor is the most frequent germ cell tumor of testis in children. For stage I yolk sac tumor of testis in children younger than 2 years, high inguinal orchiectomy alone has been the standard treatment, with a cure rate of at least 75%. Here, we compare the treatment results of receiving chemotherapy or no chemotherapy after orchiectomy, to analyze the role of chemotherapy. From February 1987 to January 1997, 22 children younger than 2 years, with stage I yolk sac tumor of testis, were included in the study. All patients had high inguinal orchiectomy without retroperitoneal lymphadenectomy. Initial diagnostic imaging studies included computed tomographic scan of abdomen, chest radiography, and long bone survey. Clinical stage I was defined as a tumor completely resected with no evidence of local regional lymph node involvement or distant metastases. Serum alpha-fetoprotein (AFP) was assessed at diagnosis. After orchiectomy, diagnosis, and staging, patients were stratified into two treatment groups, with or without chemotherapy, according to the decision of the parents. Ten children received chemotherapy consisting of cisplatin, vinblastine, and bleomycin (PVB, modified “Einhorn regimen”) for 12 weeks. The remaining 12 patients were followed up according to a “wait and see” policy. Determination of AFP was performed monthly during the first postoperative year, every other month during the second year, every 3 months during the third year, every 6 months during the fourth year, and yearly until the fifth postoperative year at least. The duration of follow-up ranged from 3 months to 119 months (median, 53 months). The Kaplan-Meier plot estimated an overall survival rate of 91.6% at 7 years after diagnosis. Among the 12 patients without chemotherapy, 2 children had relapses at 4 and 6 months after diagnosis, respectively. One was cured with PVB chemotherapy. The other patient died with refractory lung metastasis, in spite of intensive multimodality salvage therapy. The Kaplan-Meier plot showed a survival rate of 80% at 7 years and a relapse-free survival rate of 81.8% at 5 years after diagnosis. All children receiving chemotherapy were alive and free from relapse. There was no significant treatment-related toxicity. Our results may suggest that PVB chemotherapy after orchiectomy is an effective and safe regimen for stage I yolk sac tumor of testis in children younger than 2 years. Instead of four courses of PVB as used here, two or three courses could be enough. To elucidate the necessity for chemotherapy and to determine the number of courses of PVB needed (if chemotherapy is given), a randomized study of more cases is warranted.

Expression of teratocarcinoma-derived growth factor-1 (TDGF-1) in testis germ cell tumors and its effects on growth and differentiation of embryonal carcinoma cell line NTERA2/D1.

The teratocarcinoma-derived growth factor-1 (TDGF-1) gene codes for a 188-aminoacid glycoprotein that shares structural homology with the epidermal growth factor (EGF) family of growth factors. TDGF-1 is highly expressed in the undifferentiated embryonal carcinoma stem cell line NTERA2 clone D1 (NT2/D1) and its expression is downregulated in response to differentiating agents such as retinoic acid (RA) and hexamethylen-bisacetamide (HMBA). To assess the role of TDGF-1 in the onset and/or progression of human germ cell tumors, we analysed TDGF-1 expression by Northern blot and immunostaining in a panel of 59 human germ cell tumors of different histological origins. We show that TDGF-1 expression is markedly elevated in a subset of human testicular germ cell tumors as compared to normal testes. TDGF-1 overexpression occurs in about 100% of tumors with non-seminomatous phenotype, such as embryonal carcinomas and malignant undifferentiated teratocarcinomas. To address the questions of how TDGF-1 (previously called CRIPTO) may affect the growth and/or the differentiation of embryonal carcinoma cells, we have characterized the effects of exogenous recombinant TDGF-1 protein on the proliferation rate and differentiation 'potential of NT2/D1. Exogenous TDGF-1 protein stimulated DNA synthesis and cell proliferation in both undifferentiated and differentiated NT2/D1 cells. However, TDGF-1 protein treatment was unable to block differentiation induced by both RA and HMBA. These results suggest that TDGF-1 growth factor may represent an autocrine growth factor that may be involved in the process of development of testicular neoplasms.

Bipolar (neural and myoblastic) phenotype in cell lines derived from human germ cell tumours of testis.

Non-seminomatous germ cell tumours of the testis (NSGCT) form a heterogeneous group of neoplasms. Cell lines derived from NSGCT may provide useful data concerning the biology of neoplasic precursor germ cells, differentiation of tumour stem cells and the relationship between various tissue components of these tumours. Four NSGCT were studied, two mixed tumours composed of teratocarcinoma, yolk sac and trophoblastic elements, and two malignant teratomas with a massive neuroectodermal component, equivalent to primary neuroectodermal tumours (PNET) of the testis. The explanted tumours gave rise to various cell populations, including epitheloid cells, flattened large cells, spindle cells and tear drop cells of neuroblastic type. Ultrastructurally, cultured cells expressed various degrees of neural and muscular differentiation: neurosecretory granules, intermediate filaments of glial nature, and filaments resembling Z-bands. Cultured cells showed the expression of several neural and muscular markers, including neurofilaments, cytokeratin, actin, desmin, neuron-specific enolase, glial fibrillary acidic protein and HNK-1. In addition, three cases expressed HBA-71 antigen and two expressed MyoD1 protein. All cases were aneuploid, and an isochromosome 12p, i(12p), was detected in three cases. Myoblastic and neural cells are the predominant tumour cells that grow in vitro, independent of the nature and composition of the primary germ cell tumour. A histogenetic relationship between germ cell tumours and small round cell tumours of childhood is suggested.

Retrocrural lymph node metastases from testis germ cell tumours: removal via a thoraco-abdominal extraperitoneal approach after chemotherapy.

Retrocrural lymph node metastases from testis germ cell tumours: removal via a thoraco-abdominal extraperitoneal approach after chemotherapy.

Cost and risk benefit in the management of clinical stage II nonseminomatous testicular tumors

Two similarly effective treatment options exist for managing clinical low volume Stage II nonseminomatous germ cell testis tumors (NSGCT). Primary retroperitoneal lymph node dissection (RPLND) (with immediate adjuvant chemotherapy or chemotherapy at relapse) and primary chemotherapy have resulted in similar survival rates in large series. Because the chance for cure is similar with either approach, the cost and morbidity of therapy should be considered important discriminating factors in deciding which option to pursue for an individual patient. The purpose of this study was to undertake a cost/benefit and risk/benefit analysis of these two options using data and costs from the Indiana University experience. The overall direct costs for 100 patients undergoing primary RPLND were compared with the total direct costs of 100 patients receiving primary chemotherapy for low volume Stage II disease, including the costs of adjuvant chemotherapy, salvage chemotherapy in relapsing patients, and routine follow-up for a 5-year period. In addition, the two treatment options were analyzed relative to survival, late relapse, acute and chronic toxicity, (including fertility), and perioperative morbidity. In this analysis, the overall 5-year costs of RPLND were significantly less than the costs of primary chemotherapy. The two options did not differ significantly in terms of survival or quality of life. Patients receiving RPLND were found to have an advantage also in terms of fertility, toxicity, and late relapse. Treatment decisions for patients with clinical low volume Stage II NSGCT may be based on cost/benefit and risk/benefit considerations, including relative toxicity, long term cure rate, and individual patient preference. Patient compliance with follow-up, the specific expertise of the physicians, and the availability of specialized therapeutic care ultimately may influence such decisions.

Germ cell tumours in uncorrected cryptorchid testis at Institute Rotary Cancer Hospital, New Delhi.

Twenty-four out of 164 (14%) adult patients with primary germ cell tumours of testis seen over the last 6 years at the Institute Rotary Cancer Hospital (IRCH) of the All India Institute of Medical Sciences (AIIMS), New Delhi, were found to have cryptorchidism. Only one patient had undergone correction. As a result the testes were intra-abdominal in the vast majority, and patients presented late. Twenty-two patients presented with stage IIb or more advanced disease. Twelve patients had seminoma and the others had mixed or non-seminomatous germ cell tumour (NSGCT), i.e. 50% each. The earlier patients were managed by initial resection followed by radiation and/or chemotherapy. As experience grew the seven patients who presented late were given initial chemotherapy followed by resection in those with residual tumours. The probability of overall survival was 0.65 at 36 months and, was not significantly different from survival in 114 patients with tumours of normally descended testis. Early orchipexy facilitates the detection, but whether it reduces the incidence of tumours is controversial. Uncorrected cryptorchidism is now rarely seen in the West, but in India and many other developing countries tumours of uncorrected cryptorchid testes continue to be seen.

Nonseminomatous germ cell tumour of testis in Hong Kong Chinese patients.

Combination chemotherapy with multidisciplinary support results in excellent cure rate for nonseminomatous germ cell tumour of testis. 52 Chinese patients treated in two institutions in Hong Kong were reviewed retrospectively. 29 patients were stage I and IM and 3-year survival was 96% with a median follow-up of 49 months. 23 patients were stage II and above and 3-year survival was 54% with a median follow-up of 21 months. The patient details are compared with a Western population, factors influencing outcome are discussed, and provision of optimal care outlined.

Male genital cancers.

The estimated 165,000 cancers of the male genital system that will occur in the United States during 1993 represent one fourth of the expected 600,000 newly diagnosed cancers in American males for the year. Data were collected by the Surveillance, Epidemiology, and End Results (SEER) program. This paper examines histologic data collected by the SEER program from 1973-1987 and focuses on incidence, stage at diagnosis, and survival for the dominant histologic types of cancer that occur in the four major topographic divisions of the male genital system: prostate gland, testis, penis, and scrotum. Some less common histologic types within each organ are also discussed. The incidence of male genital cancer has increased rapidly over the period of study. Cancers of the prostate, most of which are adenocarcinomas, represent more than 92% of all male genital cancers. Among adolescents and young men, germ cell cancers of the testis predominate, but decline rapidly in occurrence after 40 years of age. Blacks had higher incidence rates for prostate cancer than whites; however, the situation was reversed for testicular cancer. Survival increased dramatically for testicular cancer. Cancers of the penis and scrotum of any histologic type are uncommon in the United States. The increased incidence of prostate adenocarcinomas and testis germ cell tumors indicates the need for further etiologic studies as a basis for prevention efforts.

Immunohistochemical Expression of P53 Tumor Suppressor Gene Protein in Adult Germ Cell Testis Tumors: Clinical Correlation in Stage I Disease

P53 tumor suppressor gene protein immunostaining was evaluated in the primary tumor of adult testicular germ cell cancer to assess if P53 expression would serve as a clinically useful tumor marker. Representative archival tissues from 152 orchiectomy specimens were studied for P53 immunohistochemistry. Seminoma and nonseminomatous germ cell tumor constituents revealed P53 expression via immunohistochemistry in 90% and 94% of the cases, respectively. For seminoma, there was a trend toward decreased P53 expression with advancing stage. For nonseminomatous germ cell tumor, although all cellular components showed variable P53 expression, P53 expression in embryonal carcinoma constituents increased among stages of disease. A third of pathological stage I cancer patients exhibited 2+ or greater P53-embryonal staining compared with 61% with stage II (p = 0.0670) and 67% with stage III (p = 0.0815) disease, respectively (Kruskal-Wallis, 2-sided test).As a secondary objective, we wanted to determine if P53 immunohistochemistry would be useful to predict occult disease in clinical stage I nonseminomatous germ cell tumor. This group was studied for P53-embryonal immunohistochemistry, the presence of vascular invasion and the quantitative determination of percentage of embryonal carcinoma in the primary tumor in a multivariate fashion to assess if these tests could be clinically useful to predict occult disease. Degree of P53 immunostaining of the embryonal component in the primary tumor was statistically greater for stage II by univariate logistic regression analysis (p = 0.0362). Similarly, the per cent embryonal cancer (p = 0.0002) and vascular invasion (p = 0.0005) were highly significant as predictors of occult stage II disease via the univariate testing. By multivariate logistic regression analysis, the model consisting of per cent embryonal cancer and vascular invasion provided the best prediction of occult disease in the clinical stage I cohort. In addition, this model had the highest sensitivity and specificity of all multivariate models considered. The addition of P53-embryonal staining did not improve predictability nor sensitivity/specificity.The P53 tumor suppressor gene protein is expressed to some degree in most testicular germ cell tumors and degree of staining/expression varies according to stage of disease. From the standpoint of a clinically useful primary tumor risk factor for predicting occult disease, vascular invasion by the tumor and percentage of embryonal carcinoma component in the tumor are more useful than P53 immunohistochemistry.

Neuroblastoma as a prominent component of a mixed germ cell tumor of testis

Primitive neuroectodermal tissue in teratomas of testis has been reported in the literature. A mixed germ cell tumor of testis with a prominent neuroblastoma component dictating the clinical behavior was found to be unique. Tissue sections were stained with hematoxylin and eosin, and immunohistochemical, ultrastructural, cytogenetic, and flow cytometric analyses were performed on the primitive neuroectodermal component of the testicular mass. Follow-up results at 2.5 years are included. The microscopic findings on hematoxylin and eosin slides showed cells composing the majority of the neoplasm to have features of neuroblastoma. The immunohistochemical stains showed positivity for neuron-specific enolase in the cells comprising the neuroblastoma, and transmission electron microscopic study corroborated these findings by demonstrating microtubules and rare membrane-limited, dense-core granules in the cytoplasm. Flow cytometry showed a hypertetraploid population with a large aneuploid DNA content. Cytogenetics revealed a hypertriploid modal number of 74 chromosomes. The clinical features were dictated by the neuroblastoma component in a fashion similar to that of adult neuroblastomas and responded to the chemotherapeutic regimen designed for treating neuroblastoma. The neuroblastoma component proved to be more aggressive than the other elements of this neoplasm. This finding suggests that mixed germ cell tumors showing a large neuroblastoma component should be treated promptly and aggressively with chemotherapy.

Brain metastasis as the site of relapse in germ cell tumor of testis

Brain metastases occur in approximately 8-15% of patients with testicular germ cell tumors and invariably are associated with relapse at other sites, most commonly the lungs, or as a terminal event. The authors, from the Institute Rotary Cancer Hospital, a regional cancer center in northern India, did a retrospective analysis to determine how many previously treated patients had isolated cerebral metastasis develop. Three of 123 patients with testicular germ cell tumor seen during a 6-year period starting in January 1986 had isolated cerebral metastasis develop during remission after initial treatment. Two patients who had pure seminoma were treated with radiation therapy and are alive and symptom free at 15 and 18 months. The third patient had a combined tumor, the major component of which was embryonal cell carcinoma, that required debulking surgery and radiation therapy, and the patient died with recurrent cerebral metastases. Review of the literature reveals that although cerebral metastasis is well recognized in testicular cancer, particularly nonseminomatous germ cell tumor (NSGCT), it is invariably preceded by systemic metastasis. Cerebral metastasis is extremely rare as the sole and presenting feature of relapse. This complication must be recognized and treatment defined because it may become more frequent as patients survive for longer periods with modern disease management.

Clinical profile and problems of management of 108 cases of germ cell tumours of testis at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences New Delhi 1985-1990

A retrospective analysis of 108 cases of primary germ cell tumours of testis seen over a 6 year period at Institute Rotary Cancer Hospital of All India Institute of Medical Sciences, New Delhi is presented. There were 45 (42%) cases of seminoma and 63 (48%) of non-seminomatous germ cell tumours (NSGCT). The median age at presentation was 35 and 30 years respectively. Almost half (56) patients presented in advanced stage (stages IIc-IV). Tumours in undescended testis formed an important subgroup (14%). The standard approach of treatment was radiotherapy in stages I & II seminomas and chemotherapy in bulky seminomas and metastatic NSGCT. Chemotherapy protocols used were VAB-6 and PVB. Although a policy of surveillance has been practised for stage I NSGCT, it is debatable whether it is universally suitable for our patients. The results of treatment in low volume disease are comparable to that in the west but the management of bulky disease requires a more aggressive approach. Unfortunately only 74 out of 108 (68.5%) patients were able to complete the treatment prescribed. Most of the defaulters were from the chemotherapy group because of inability to afford the drugs. The probability of survival of those who completed treatment was 0.77 at 4 years. Since testicular tumours are largely curable, a more vigorous policy of detection, follow up and treatment needs to be pursued. Better screening of children with undescended testis will reduce cancer in this group. Failure to provide chemotherapy to all patients is particularly unfortunate for a curable disease like testis cancer.

Analytical bias by contamination from hemolysis in determination of serum lactate dehydrogenase isoenzyme 1 in patients with testis germ cell tumors.

We investigated the impact of correction for contamination from hemolysis on serum lactate dehydrogenase isoenzyme 1 (S-LD-1) determinations. A study of hemolysates from 7 control patients showed a mean correction factor for the contamination of 0.1 U/L S-LD-1 for each 1 mg/L serum hemoglobin (S-Hb). S-LD-1 in a series of blood samples from 44 patients (EJC 1992;28:410-5) would decrease median 24 U/L (range 8-70 U/L) if the measurements were corrected with this factor. So we advice to correct S-LD-1 determinations for the contamination with a common correction based on the S-Hb concentrations in the samples.

Usefulness of inferior mesenteric artery preservation in retroperitoneal lymph node dissection

— In stage II and III non-seminomatous germ-cell testis tumor, retroperitoneal lymph node dissection is generally advised, often associated with systemic chemotherapy. Most Authors report ligature and section of the inferior mesenteric artery without any complication. We reviewed some papers by Valdoni and co-workers about preservation and peeling of the afore-mentioned artery in colo-rectal radical surgery; such procedure is technically feasible and oncologically reliable and ensures good perfusion of the descending colon, especially in the case of vascular anomalies (accessory left colic flexure artery, mono- or bilateral absence of middle rectal artery). In fact those patients subjected to retroperitoneal lymph node dissection may request colonic resection in the future; therefore preservation of the inferior mesenteric artery may represent an example of surgical foresight.

Predictive factors for effective salvage therapy of nonseminomatous germ cell tumors of testis.

Twenty-four patients with metastatic and chemotherapy-refractory nonseminomatous germ cell tumors of the testis were treated with various chemotherapy regimens upon failure. Eight of the 24 patients (33%) are alive and disease-free after salvage therapy with a median follow-up of sixteen months. Prognostic factors tested included those known to be predictive for initial response to therapy (clinical stage and degree of elevation of the biomarkers). In addition, time to initiation of salvage therapy and response to initial chemotherapy were assessed as variables. Our data suggest that patients with solitary organ metastases following relapse, and response to initial chemotherapy are favorable predictors for response to salvage treatment. All the patients with solitary organ metastases (5/5 [100%]) but only 3/19 (16%) of the patients with multiple metastatic sites were salvaged. Patients with delayed initiation of salvage therapy had a reduced likelihood of achieving a complete remission but this was not statistically significant. The variables identified need to be incorporated into future trials testing the efficacy of salvage therapy for patients with nonseminomatous tumors of the testis.

The Role of Alkaline Phosphatase Isoenzymes as Tumor Markers for Testicular Germ Cell Tumors

The role of serum alkaline phosphatase as a tumor marker for testicular germ cell disease was investigated in 26 patients with testicular seminoma and 13 with nonseminomatous germ cell testis tumors. Placental alkaline phosphatase-like enzyme was elevated in 50% of the stage I seminoma patients and in all patients with stages II to III disease. In addition, liver (tissue unspecific) alkaline phosphatase was elevated in 10 and 83% of the patients, respectively. Lactic dehydrogenase and β-human chorionic gonadotropin (β-HCG) were detected in 50 to 60% of the patients with stage I seminoma. By combining placental alkaline phosphatase-like enzyme, lactic dehydrogenase and β-HCG, 75% of the stage I and 100% of the stages II and III seminoma patients could be identified correctly. Placental alkaline phosphatase-like enzyme in serum also occurred with nonseminomatous germ cell tumor but less frequently, while liver alkaline phosphatase was not detected at all. Thus, placental alkaline phosphatase-like enzyme and liver alkaline phosphatase were predominantly determined in the serum of patients with seminoma.In studies of tumor tissues from 31 of these patients, those with normal serum placental alkaline phosphatase-like enzyme levels had significantly lower tissue placental alkaline phosphatase-like enzyme levels than patients with elevated serum levels (p <0.01). Seminoma tissues showed significantly higher levels of placental alkaline phosphatase-like enzyme and liver alkaline phosphatase than nonseminomatous germ cell tumors (p <0.01), explaining the infrequent elevation of serum placental alkaline phosphatase-like enzyme and liver alkaline phosphatase found in patients with nonseminomatous germ cell tumors.

Germ cell tumor of testis in a patient with von hippel-lindau disease

Germ cell testicular tumor is a previously undescribed entity in association with von Hippel-Lindau disease. This case exemplifies the variety of pathologic entities encountered in von Hippel-Lindau disease and stresses the importance of thorough evaluation of the patient, as well as careful follow-up, to ensure early detection of potentially malignant lesions.