Nonseminomatous germ cell testicular tumors clinical stage I: differentiated therapeutic approach in comparison with therapeutic approach using surveillance strategy only.

Surveillance after orchiectomy alone becomes popular for the management of clinical stage I nonseminomatous germ cell testicular tumors (CS I NSGCTT). Effort to identify patients at high risk of relapse leads to searching for risk factors of CS I NSGCTT. The aim of the study was to analyse own long-term experiences with different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression and to correlate these results with the group of patients who were treated with surveillance strategy only. From 11/1984 to 12/1991 a total of 145 patients with CS I NSGCTT were treated with surveillance strategy only (group A) and were followed-up to 1/2007. Patients, who had the disease progression, were treated with systemic chemotherapy. The disease progression was experienced in 52 patients (35.9 %). The overall survival rate of the patients in this group was 130/145 (89.7 %). From 1/1992 to 1/2007 a total of 323 patients with CS I NSGCTT were stratified to different risk-adapted therapeutic approaches (groups B1-3) according to histopathologic findings of primary tumor removed by inguinal orchiectomy. 111 patients (group B1) with vascular invasion and majority of embryonal carcinoma component in the primary tumor were treated with adjuvant chemotherapy (2 cycles of BEP). Disease progression developed in two patients (1.9 %). Other patients live without evidence of disease (NED). None of them died. Among 11 patients (group B2) with vascular invasion and majority with teratomatous elements in the primary tumor underwent primary retroperitoneal lymph node dissection (RPLND), 9 were found to be pathological stage I. The disease progression was observed in two patients (18.2 %), they died 87-122 months following orchiectomy. Two patients (18.2 %) with pathological stage II received adjuvant chemotherapy. Other 7 patients live with NED following RPLND. 201 patients (group B3) without vascular invasion have been followed after orchiectomy alone. They were kept under close surveillance, consisting of regular follow-up with tumor markers, chest x-ray and CT of the retroperitoneum. The disease progression was observed in 39 patients (19.4 %), who were treated with BEP chemotherapy. Three of them (7.7 %) died after a mean follow-up of 32.7 months following orchiectomy. The overall survival rate of all patients in group B1-3 was 98.4 %. Introduction of different therapeutic approaches in CS I NSGCTT patients according to risk factors of the disease progression might reduce the overall relapse rate of these patients from 35.9 % (group A) to 19.4 % (group B3) (P< 0.001). Surveillance procedure is recommended only in patients without vascular invasion in the primary tumor.

Cystic dysplasia of the rete testis. Case report.

Cystic dysplasia of the rete testis (CDRT) is a very rare cause of a paediatric scrotal mass often associated with renal and other genitourinary tract anomalies. These complex malformations are probably due to a developmental defect of the mesometanephric system during embryogenesis. A case of asymptomatic scrotal swelling in a 4-year-old boy is presented. Ultrasonography, showed a cystic lesion of the left testis associated with absence of the left kidney. Orchiectomy was performed because of extensive gonad involvement. Pathologic examination revealed multiple, anastomosing, irregular cystic spaces of varying sizes and shapes predominantly located in the region of the rete testis. The cysts had spread irregularly, displacing the testicular parenchyma, which was subsequently compressed under the tunica albuginea. Preoperative diagnosis of CDRT is easy if age, precise localisation, characteristic ultrasonographic features and other genitourinary malformations are considered. Other paediatric cystic lesions should be included in the differential diagnosis. It is possible to cure CDRT by orchiectomy or by conservative treatment. Nowadays the later option is preferred, but diagnosis of CDRT must be precisely established and followed by careful monitoring.

Germline mutation of the RET proto-oncogene in members of Slovak families with multiple endocrine neoplasia 2.

Detection of mutations in RET proto-oncogene in Slovak families from different localities and of different ethnic origin with MEN 2 syndrome is reported. Despite the fact that the same mutation of RET oncogene was found in different family members, the latency period of tumor appearance and their pathogenicity differed substantially. In addition, also different phenotypes of the disease were expressed in various family members having the same RET gene mutation. The data indicate that the mechanism of MEN2 syndrome is not only due to the RET gene mutation, and strongly support the conclusion that additional genetic events are involved in the disease formation.

Prognostic factors in clinical stage I nonseminomatous germ cell testicular tumors: rationale for different risk-adapted treatment.

OBJECTIVE: Surveillance after orchiectomy alone becomes popular for the management of clinical stage I nonseminomatous germ cell testicular tumours (CS I NSGCTT). Effort to identify patients at high risk of relapse leads to searching prognostic factors of CS I NSGCTT. The aim of this study was to identify those patients in whom a surveillance policy is less likely to be successful. PATIENTS AND RESULTS: Seventy-two CS I NSGCTT patients were stratified to different risk-adapted therapeutic approaches according to histopathologic findings of primary tumor removed by inguinal orchiectomy. Eighteen patients (group A) with vascular invasion and majority of embryonal carcinoma component in the primary tumor were treated with adjuvant BEP chemotherapy. None of them experienced disease progression after a median follow-up period of 36 months after orchiectomy. Five patients (group B) with vascular invasion and the majority of teratomatous elements in the primary tumor have been followed up 56 months after orchiectomy. They were treated with primary retroperitoneal lymph node dissection (RPLND). Two of them (40%) had pathologic stage II after RPLND and underwent subsequent chemotherapy. One of them died due to disease progression 29 months following orchiectomy. Another one lives with no evidence of disease (NED). Three patients in pathologic stage I are alive with NED. Forth-nine patients (group C) without vascular invasion have been followed up for a median duration of 37 months after orchiectomy. They were kept under close surveillance, consisted of regular follow-up with tumor markers, chest x-ray and CT of the retroperitoneum. Disease progression was observed in 7 (14.3%) patients after a median duration of 8 months after orchiectomy. They were treated with BEP chemotherapy and live with disease-free median survival of 22 months after completion of therapy. The overall survival rate of all 72 patients was 98.6%. The median survival for all patients was 37 months (range 7-73). CONCLUSIONS: The authors will continue to use surveillance policy only in patients without vascular invasion in the primary tumor.

Familial testicular cancer and developmental anomalies.

Familial occurrence belongs to factors followed in etiology and pathogenesis of testicular germ-cell tumors. Association with abnormal testicular development, or with other risk factors is relatively frequent. In our material 650 patients had been treated for testicular cancer in the period of 1981-1995. Familial occurrence was observed 7-times (1.08%), most frequently in combination with cryptorchidism. Individual families were analyzed in details, including HLA typing. On basis of the observations the supplementation of initial examination of each patient with suspicious testicular cancer with detailed familial history aimed also at the occurrence of urogenital developmental anomalies and tumors has been recommended. The knowledge about familial tumor occurrence in the first-degree relatives in combination with thorough testicular self-examination is being considered of great importance in the secondary prevention.

[Results of long-term follow-up of surgical treatment of pulmonary metastases of testicular germ cell tumors]. / Vysledky dlhodobych sledovaní chirurgickej liecby plúcnych metastáz germinatívnych nádorov testis.

The authors analyse 34 cases of surgeries performed due to residual pulmonary metastases with germinative testicular tumours. Good results in the length of survival are ascribed to thoracotomy, or sternotomy with the resection of metastatic foci, i.e. the only method which reliably ascertains the biological nature of residual pulmonary lesion after chemotherapy. (Tab. 1, Fig. 2, Ref. 17.)

Management of germ cell testicular cancer with pulmonary metastases.

Twenty eight patients with germ cell testicular cancer pulmonary metastases received primary chemotherapy including bleomycin, etoposide, and cisplatin (BEP). Complete response was achieved in 21 (75%) patients, in 11 of them CR was achieved following chemotherapy alone. Postchemotherapy surgery of residual mass was performed in 12 (42.9%) patients with normalized serum tumor markers. Retroperitoneal lymph node dissection was performed in one patient, pulmonary surgery in four, and both postchemotherapy treatments in 7 patients. Overall cure rate was 89.3%, 26 (92.9%) patients are still alive at a mean follow-up of 19.7+ months (range, 3-34+ months) after the treatment start. Two (7.1%) patients died: one of them due to disease progression during chemotherapy, and the second one due to postoperative complication (acute respiratory failure). Relapse of disease was observed in one patient 21 months following CR achievement, and sequential chemotherapy was introduced. Authors recommend surgical remove of all radiologically detected residual deposits, because the available imaging methods are not adequate for determining the histologic composition of residual mass, which is decisive for further therapy and has prognostic value.

[Familial occurrence of tumors and developmental anomalies of the testis]. / Familiárny výskyt nádorov a vývojových anomálií testis.

BACKGROUND: Family occurrence ranks belong the factors followed in etiology and pathogenesis of germ-cell tumours of the testis. Its association with abnormal testicular development, respectively with other risk factors is relatively frequent. OBJECTIVES: The aim of this study was to indicate this coherence by means of case histories of author's patients and to propose further procedures. METHODS AND RESULTS: There were 535 patients treated for testicular cancer in the period of 1982-1994. Family occurrence was observed in 6 cases (1.12%), most frequently incombination with maldescensus testis. Individual families were analysed in detail, including HLA typization. Bilaterality of testicular cancer was observed in two brothers who were HLA identical. Other two brothers had the history of bilateral maldescensus testis, one of whom was subdued to bilateral orchiectomy in childhood, the other at the age of 16, a tumour in one testicle following orchidopexy performed in childhood. The history of maldesensus testis was observed in four members of another family, two of whom developed tumours. CONCLUSIONS AND MEANING FOR PRACTICE: Authors recommend supplementation of the initial examination of each patient with suspective testicular cancer with detailed family history aim at the occurrence of urogenital anomalies and tumours. General knowledge of the first-degree relatives about the possibility of family occurrence of tumours, and instructions for testicular self-examination are considered as the most suitable method from the stand point of secondary prevention. (Ref. 21.)

Postchemotherapy surgery in nonseminomatous testicular tumors.

Two hundred and twenty patients with metastatic nonseminomatous germ cell testicular tumors received primary chemotherapy including cisplatin, vinblastine and bleomycin (PVB). Complete response was achieved with chemotherapy alone in 108 (49.1%) patients. Postchemotherapy surgery of the residual mass was done in 85 (38.6%) patients with normalized serum tumor markers. Laparotomy was done in 62 patients, 19 patients underwent thoracic surgery, and 4 patients had both postchemotherapy treatments. Thirteen (5.9%) patients had persistently elevated serum tumor markers, they died despite salvage second-line chemotherapy. Fourteen (6.4%) patients died during primary PVB chemotherapy. The masses removed at laparotomy consisted of necrotic and/or fibrotic tissue in 25.8%, mature teratoma in 61.3% and viable cancer was detected in 12.9% of cases. In contrast, resected pulmonary masses consisted of necrotic and/or fibrotic tissue in 42.1%, mature teratoma in 26.3% and viable cancer in 31.6%. The total therapeutic outcome in 220 patients was as follows: 159 (72.3%) patients are alive and free of disease; 4 (1.8%) patients live with disease, and 57 (25.9%) died of the disease.

Expression of the alpha 2-macroglobulin receptor on human neoplastic fibroblastoid cells.

The alpha 2-macroglobulin membrane-associated receptor (alpha 2MR) has been previously detected on hepatocytes, fibroblasts, macrophages, syncytiotrophoblasts and recently on human malignant blood cells of myelomonocytic leukemia. In cells growing in vitro from human germ cell tumors alpha 2MR mRNA was detected by Northern blotting. Endocytosis of alpha 2M from culture medium was detected in these cells by indirect immunofluorescence. In cell extracts alpha 2M and its degradation products were detected by immunoblotting. The cells expressing alpha 2MR and internalizing alpha 2M were identified as fibroblasts both by their morphology and expression of vimentin intermediate filaments. The role and function of alpha 2MR receptor in the analyzed neoplastic cells of teratomatous origin is discussed.

Seminomas of the canine testis. Counterpart of spermatocytic seminoma of men?

BACKGROUND: Dogs develop germ cell tumors of the testis at a relatively high rate. It is not known to what degree these tumors resemble various human testicular neoplasms. EXPERIMENTAL DESIGN: The epidemiology and morphology of a series of spontaneous canine testicular tumors, collected between 1985 and 1991, was analyzed, and compared with human testicular germ cell tumors. DNA content analysis of representative samples was performed using flow cytometry and image cytometry. Eight human spermatocytic seminomas were studied in parallel. RESULTS: All canine tumors had the histopathologic features reported as typical for dog testis seminomas. These tumors could show both an intratubular and an invasive component. Most of them were pure (78%), while they could be combined with a Leydig cell tumor, a Sertoli cell tumor, or both. No somatic, placental or yolk sac cells were identified, and there was no carcinoma in situ (CIS). A bimodal age distribution, with a peak around 1 year of age and between 4 and 16 years of age, was found for all pure and mixed testicular tumors, except for those composed of a Leydig cell and a seminoma component. These tumors were all present in dogs older than 7 years, being significantly more older (p < 0.01) than dogs with a pure tumor of either type. All Sertoli cell and Leydig cell tumors were diploid. No consistent peritriploid DNA content, characteristic of human testicular germ cell tumors, was found for canine seminomas, which most often had a diploid DNA content. Human spermatocytic seminomas always contained diploid tumor cells, and showed a relatively low number of high ploidy cells, comparable to canine seminomas of the testis. CONCLUSIONS: The so-called seminomas of the testis are tumors of old age. Histologically, these tumors are composed of a single cell type with some variation without evidence of differentiation. It is proposed that canine seminoma correspond to human spermatocytic seminomas. It is thought that the Leydig elements in these tumors represent a reactive change rather than biphasic differentiation of a single stem cell capable of germinal and sex-cord cell development.

The complex formation of influenza virus envelope glycoproteins with outer membrane proteins of Neisseria meningitidis or Borrelia burgdorferi.

The isolation of influenza virus envelope glycoproteins was achieved by one-step procedure consisting of treatment of purified virus with zwitterionic detergent and separation of viral constituents by sucrose density gradient centrifugation. Viral glycoproteins and proteins of outer membrane of N. meningitidis or B. burgdorferi formed complexes after removal of the detergent by dialysis. Complexing of viral glycoproteins and bacterial proteins was monitored by gel chromatography on Sepharose 6B, polyacrylamide gel electrophoresis and electron microscopy. It was demonstrated by immunoblot analysis, that virus-spirochete complexes elicited formation of antibodies in mice directed against osp A and osp B of spirochete, as well as against viral glycoproteins, respectively.

[Postchemotherapy surgery in patients with non-seminomatous testicular tumors]. / Postchemoterapeutická chirurgia u pacientov s neseminomatóznymi nádormi testis.

From 1982 to 1993, 220 patients with metastatic nonseminomatous germ cell testicular tumours were treated with a combination of cisplatin, vinblastine and bleomycin. Complete remission was achieved in 108 (49.1%) pts. on chemotherapy alone. Residual abdominal or pulmonary masses persisted on completion of chemotherapy in 85 (38.6%) pts. All of them had normal serum levels of tumour markers. In 13 (5.9%) pts tumour markers were positive. Fourteen (6.4%) pts died during primary chemotherapy. The pts with residual masses and normal tumour markers were treated by surgical exploration and masses removal. In 62 pts the masses were resected through laparotomy, in 19 pts through pulmonary surgery and in four pts laparotomy was followed later by pulmonary surgery. The masses removed at laparotomy consisted of necrotic and fibrotic tissue in 25.8%, mature teratoma in 61.3% and viable cancer was detected in 12.9% cases. In contrast, resected pulmonary masses consisted of necrotic and fibrotic tissue in 42.1%, mature teratoma in 26.3% and viable cancer in 31.6%. The total therapeutic outcome in 220 pts was as follows: 159 pts (72.3%) are alive and free of disease. Four pts (1.8%) live with the disease and 57 pts (25.9%) died from the disease. On the basis of their results the authors advocate: 1. Primary chemotherapy should be indicated for IIA and IIB stages of nonseminomatous testicular tumours. 2. Surgical exploration should be reserved for pts with residual abdominal and pulmonary masses bigger than 15 mm in diameter. 3. Operation should include a complete removal of all residual masses. 4. No reliable criteria indicating necrotic and fibrotic changes preoperatively were identified. (Tab. 4, Ref. 17.)

Bilateral germ cell tumors of the testis.

In a retrospective study of 530 patients with testicular germ cell tumors treated between 1977 and 1993, a group of 12 patients (2.26%) with bilateral testicular tumors was analyzed. While bilateral tumors were simultaneously present in two cases (both with different histologic types), consecutive development of a tumor in the contralateral testis was observed in 10 patients 5.25 years (range, 3-13.5 years) after orchiectomy for the first tumor. The authors highlight the variability of histologic types in both testes, the need for an individual therapeutic approach with a view to previous therapy for the first tumor, the need for hormonal replacement as well as the possibility of testicular prosthesis implantation following bilateral orchiectomy.

Neo-adjuvant chemotherapy with delayed orchiectomy in patients with advanced germ cell testicular cancer.

A total of 13 patients with advanced germ cell testicular cancer underwent initial PVB chemotherapy without previous orchiectomy. Complete response (CR) of metastases was observed in 5 patients following chemotherapy alone. The residual mass persisted in 8 patients (in 5 of them in the retroperitoneum, in two patients in the lungs only and in one patient in both localizations). The residual masses were removed surgically. There were no viable malignant tumors in the removed tissue on histological examination. Delayed orchiectomy was performed simultaneously with surgical removal of the residual mass in the retroperitoneum or in the lungs in 8 patients, and in 5 patients as a separate procedure in complete responders following chemotherapy alone. Residual viable tumor in the testis was found in three patients, necrotic or fibrotic tissue in 5 patients, and mature teratoma in 5 patients. In patients with advanced germ cell testicular cancer preference must be given to early beginning of intensive chemotherapy without tissue diagnosis of primary tumor by orchiectomy. Benefit of this therapeutic approach is the timely management of acute abdominal and/or pulmonary symptoms of life-threatening distant metastases.

Chemotherapy of testicular cancer: 10-year experience.

A total of 250 patients with germ cell testicular tumors were treated by PVB chemotherapy between 1982 and 1992. Mean age of patients was 28.9 years (range 15-52). Thirty-four patients in clinical Stage II (11 patients IIA, 13 patients IIB, and 10 patients IIC) underwent primary retroperitoneal lymphadenectomy (RPL) with subsequent chemotherapy. They were followed-up for a mean of 106.3 months (range 85-125). CR was achieved in 30 patients (88.2%). Three patients relapsed. Twenty-seven patients (79.4%) are alive with no evidence of disease (NED) after a minimum of 5 years since the start of therapy. One hundred and twenty-two patients underwent primary chemotherapy for clinical Stages IM (15 patients), IIA (31 patients, IIB (48 patients) and IIC (28 patients) with RPL in cases with residual mass in the retroperitoneum. They were followed-up for a mean of 47.7 months (range 6-122). CR was achieved in 115 patients (92.7%) (75 of them received chemotherapy alone, 40 patients achieved CR following combined cytostatic-surgical treatment). Eleven patients relapsed. One hundred and nine patients (89.3%) are alive with NED. Ninety-four patients in Stages III and IV (8 patients III, 86 patients IV) underwent primary chemotherapy with additional surgical removal of residual metastases. They were followed-up for a mean of 50.5 months (range 6-125). CR was achieved in 65 patients (69.1%) (32 of them received chemotherapy alone, 33 patients achieved CR following combined cytostatic-surgical treatment). Eleven patients relapsed. Fifty-seven patients (60.6%) are alive NED. There were 11 patients with advanced germ cell testicular cancer (Stages IIC and IV) who underwent initial PVB chemotherapy without previous orchiectomy. Delayed orchiectomy was done simultaneously with surgical removal of residual mass in the retroperitoneum or in the lungs or at completion of chemotherapy alone. The toxicity of chemotherapy was moderate. There were drug-related deaths in ten patients (4%).

Malignant granulosa cell tumor of the testis associated with gynecomastia and long survival.

A case is reported of classic granulosa cell tumor of the testis with metastases to the retroperitoneal lymph nodes occurring in a 26-year-old man. The patient had left-sided testicular enlargement and bilateral gynecomastia. He was treated by radical orchiectomy, retroperitoneal lymph node dissection, and radiation therapy and is well without evidence of disease 14 years after diagnosis. This is the first documented case of granulosa cell tumor of the testis with metastases and long remission after successful therapy to the authors' knowledge.

Monitoring of patients with non-seminomatous germ cell tumors of the testis by determination of alpha-fetoprotein and beta-human chorionic gonadotropin levels and by computed tomography.

The results of a 7-year monitoring of 230 patients with non-seminomatous testicular tumors are reported with respect to the employment of radioimmunoanalysis of alpha-fetoprotein and beta-human chorionic gonadotropin levels and CT examinations of retroperitoneum and lungs. Prior to orchiectomy, elevated levels of at least one of these markers were found in 79% of patients. After orchiectomy, tumor marker levels were in 70.4% of patients in agreement with the results of CT examinations. After the completion of chemotherapy, in more than a half of patients normal tumor marker levels and positive CT findings were observed. These results were most often due to the presence of mature teratoma. In Stage I patients the advantages of tumor marker determinations and CT examinations in the early detection of tumor progression have fully been confirmed.

Primary chemotherapy in the management of low stage (IIA and IIB) non-seminomatous germ cell testicular tumours.

In a prospective study a total of 65 patients in clinical stages IIA and IIB nonseminomatous testicular tumours were treated by primary chemotherapy followed by retroperitoneal lymphadenectomy in cases with residual disease. The patients were given a combination of cisplatin, vinblastine and bleomycin, or also etoposide. Sixty-two patients (95.4%) achieved complete response: 39 (60%) by chemotherapy alone and 23 (35.4%) following surgical removal of residual disease. Three patients died; there were two drug-related deaths during PVB chemotherapy, one patient had progression of disease following chemotherapy and died as a result of disease dissemination. Three patients relapsed from complete response following chemotherapy, two of them died within 19 and 29 months after the onset of therapy. The third patient received second-line chemotherapy and gained complete response again. Of the 65 patients, 60 (92.3%) survive with no evidence of disease. The follow-up period ranged from 6 to 79 months (mean 39.4 months, median 39 months).

[Combined therapy in patients with testicular germ cell tumors in the dissemination stage (pulmonary metastasis)]. / Kombinovaná liecba pacientov s germinatívnymi nádormi testis v stádiu diseminácie (pl'úcne metastázy).

The efficacy of combined cytostatic-surgical treatment was evaluated in a prospective study involving 70 patients with germinal tumors of the testis metastasizing into the lungs. Complete remission was achieved in 50 (71.4%) patients, 30 of these received only chemotherapy. Thoracotomy was performed in 14 patients with residual pulmonary CT finding, 6 of them underwent bilateral operations. Of the total 21 operations of the lungs residual malignant tumor was found 4 times. After a mean follow up period of 29.8 months since onset of treatment 48 patients (68.6%) survived. Within a mean of 11.4 months after onset of treatment 22 patients (31.4%) died. The authors consider thoracotomy with resection of the metastatic focus to be the only method for determining reliably the biological nature of the residual pulmonary lesion after chemotherapy. The result of the procedure determines the further measures, i.e. sequential chemotherapy or regular check ups. (Tab. 1, Fig. 6, Ref. 15.).