Non-germ Cell Research Articles

Testicular cancer: the quest continues.

Treatment for testicular cancer has dramatically improved during the last 15 years. Much of this success has come about because of improved staging and operative techniques but, most importantly, through the introduction of successful systemic chemotherapy. Nonetheless, relevant issues still remain to be addressed in regard to the optimal therapy for patients with germ cell neoplasms. Included in these issues is delineating the most effective but minimally morbid treatment for patients with early-stage and low-volume metastatic disease while continuing to create innovative treatment approaches for poor-risk patients with metastatic disease. The unique association of primary mediastinal germ cell neoplasms with the development of non-germ cell cancers and Klinefelter's syndrome may provide some early clues for the determination of factors controlling differentiation. These observations issue a challenge to both clinical and preclinical researchers involved in the study of this neoplasm.

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.

Intermediate filaments and desmosomal plaque proteins in testicular seminomas and non-seminomatous germ cell tumours as revealed by immunohistochemistry

Seminomas and non-seminomatous testicular germ cell tumours were studied for the presence of cytokeratin and vimentin filaments and desmosomes using immunohistochemical methods. In the majority of the classical seminomas and in seminomatous area of mixed tumours most tumour cells appeared to lack cytokeratin filaments. Some seminomas contained a focally variable proportion of cells exhibiting cytokeratin-positive structures while other cases contained only few seminoma cells with a well developed fibrillar cytokeratin network. Gel electrophoresis of cytoskeletal proteins from microdissected regions revealed cytokeratin polypeptides nos. 8 and 18 typical of simple epithelia. In one seminoma, however, all, or almost all, tumour cells contained cytokeratin filaments. This finding is in line with the assumption of transitional forms between seminoma and embryonal carcinoma. Despite the lack - or variable expression - of cytokeratin filaments most seminoma cells contained desmosomes, although often few in number and irregularly distributed at the circumference of the cells. Loosely arranged and often very sparse vimentin fibrils were found in many, but not all seminoma cells. Double label immunofluorescence microscopy suggested that the majority of desmosomes was associated with intermediate filaments of the vimentin type. In contrast, in carcinoma cells of malignant teratomas, in well differentiated epithelial cells of intermediate-type malignant teratomas and in trophoblastic cells present in trophoblastic-type malignant teratomas cytokeratin filament bundles as well as desmosomes were decorated. The arrangement and density of the cytokeratin filament skeleton and of desmosomes varied with degree of maturation of the tissue. The most regular distribution and intensive staining of cytokeratin filaments and desmoplakin was found in "mature" tissues. Vimentin was demonstrated in mesenchymal areas and stroma cells. The results show that seminomas are distinguished from most other germ cell and non-germ cell tumours by the presence of true desmosomes together with scanty vimentin filaments in most tumour cells. In addition, they indicate that seminoma cells can be heterogeneous in their cytoskeletal complement and may include cells with cytokeratin expression, indicative of a multipotential character of the initially transformed cell(s).

Resection of thoracic and abdominal teratoma in patients after cisplatin-based chemotherapy for germ cell tumor: Late results

Fifty-one patients with primary testicular (N = 46) or mediastinal germ cell cancer (N = 5) were treated from April, 1975, through May, 1981, and had teratoma resected from residual disease after cisplatin-based combination chemotherapy. All patients had normal serum markers before resection of pulmonary (N = 12), mediastinal (N = 5), thoracoabdominal (N = 8), supraclavicular (N = 1) or abdominal disease (N = 25). Teratoma was classified as mature teratoma (N = 29), immature teratoma (N = 15), or immature teratoma with non-germ cell elements (N = 7). Thirty of 51 (60%) patients remain free of recurrent disease, whereas 20 patients have either recurrent carcinoma (N = 10) or teratoma (N = 10). One patient has a presumed second malignancy. After additional chemotherapy, four patients with recurrent carcinoma are alive and disease free and six have died. After an additional operation, eight of 10 patients with recurrent teratoma are long-term survivors. In four patients the initial relapse of carcinoma developed more than 2 years after therapy; in an additional patient carcinoma recurred after a 32 month disease-free survival period. Univariate factors predicting for relapse include tumor burden, immature teratoma with non-germ cell elements, and site (mediastinum), whereas only immature teratoma with non-germ cell elements and site predicted for survival. Immature teratoma and mature teratoma had similar relapse-free intervals and overall survival intervals. According to a multivariate analysis, primary tumor site at the mediastinum is the most significant adverse factor predictive for both relapse and survival (two of five patients survived). This study appears to support the various preclinical models that demonstrate multipotential capabilities of teratoma. Complete surgical excision of teratoma remains the most effective treatment with continued close follow-up recommended for high-risk patients (immature teratoma with non-germ cell elements, large tumor burden, or primary mediastinal tumors.

Karyotyping and DNA flow cytometry of mature residual teratoma after intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis: A report of two cases

Karyotyping and DNA flow cytometry was performed on mature residual teratoma cells following intensive chemotherapy of disseminated nonseminomatous germ cell tumor of the testis to study its biology. We report herein a successful method for short-term tissue culture and karyotyping of retroperitoneal residual mature teratoma in two cases. In vitro morphology confirmed that the cultured cells were nonembryonal carcinoma cells. Both mature residual teratomas were highly aneuploid and possessed the i(12p) marker characteristic of testicular germ cell tumors. A clone in the retroperitoneal residual lesion of one of the patients showed a DNA-index different from the primary tumor and might represent a clone unmasked by chemotherapy. In view of these data, which are in agreement with recent reports on secondary non-germ cell malignancies arising in mature residual teratoma, agressive surgery of mature residual lesions seems justified.

Teratoma Following Cisplatin-Based Combination Chemotherapy for Nonseminomatous Germ Cell Tumors: A Clinicopathological Correlation

From April 1975 through May 1981, 51 patients had teratoma resected from residual disease following cisplatin-based combination chemotherapy. All patients had normal serum markers before resection of abdominal (25), lung (12), mediastinal (5), thoracoabdominal (8) or other (1) disease. Teratoma was classified as mature in 29 cases, immature in 15 or immature with nongerm cell elements in 7. Of the 51 patients 31 (61 per cent) remain free of recurrent disease, while 20 either had recurrent carcinoma (10) or teratoma (10) requiring further therapy. Nine patients died, including 1 in whom angiosarcoma developed, which was thought to be secondary to previous radiation therapy. In 4 patients the initial relapse of carcinoma developed beyond 2 years after resection.Univariate factors predicting for relapse include tumor burden, immature teratoma with nongerm cell elements and site (mediastinum), while only immature teratoma with nongerm cell elements and site predicted for survival. Patients with immature teratoma had a comparable relapse-free and over-all survival as those with mature teratoma. Using a multivariate analysis, primary tumor site at the mediastinum was the most significant adverse factor predictive for relapse and survival. This study appears to support the various pre-clinical models that demonstrate multipotential capabilities of teratoma. Complete surgical excision of teratoma remains the most effective treatment with continued close followup recommended for high risk patients (immature teratoma with nongerm cell elements, large tumor burden and primary mediastinal tumors) with resected teratoma.

Alpha-fetoprotein-producing pancreatoblastoma. A case report

A case of pancreatoblastoma, arising in the tail of the pancreas with metastases to the right radius, in an 8-year-old boy is reported. The serum alpha-fetoprotein (AFP) level was over 13 times the normal value before surgery, but returned to normal after removal of the primary tumor. Furthermore, AFP was detected in tumor tissue by immunohistochemistry. This case, representing the second primary non-germ cell pancreatic neoplasm in a child producing elevated serum AFP, supports the use of serum AFP in diagnosing this lesion.

Differential diagnosis and therapy of rare testicular tumors.

The origin, differential diagnosis and therapy of rare testicular tumors are reviewed. 5% of all testicular tumors are rare tumors. Most of these rare tumors are of non-germ cell origin.

Human chorionic gonadotropin and human placental lactogen in extragonadal tumors an immunoperoxidase study of ten non-germ cell neoplasms

The immunoperoxidase localization of the alpha and beta subunits of human chorionic gonadotropin (hCG) and of human placental lactogen (hPL) was studied in ten extragonadal nontrophoblastic tumors associated with raised serum levels of one or more of these placental proteins. Three of the tumors were bronchial carcinomas, one was a gastric carcinoma, two were malignant carcinoids (one bronchial and one gastric), two were pancreatic islet cell carcinomas, and two were metastatic carcinomas with an unknown primary site. The maximum alpha subunit serum level was 33,000 ng/ml (gastric carcinoid), the maximum hCG/hCG-beta level was 705,000 ng/ml, and the maximum hPL level was 50 ng/ml (both in the gastric carcinoma). An indirect immunoperoxidase technique and rabbit polyclonal affinity-purified antibodies and peroxidase conjugates were used on formalin-fixed, paraffin-embedded sections. Five blocks (eight cases) or six blocks (two cases) from various sites were obtained from each patient at surgery and/or autopsy. Positive stains for hCG/hCG-beta were seen in six of seven tumors (25/37 blocks) with raised levels, for the alpha subunit in nine of nine tumors (30/47 blocks), and for hPL in two of five tumors (4/26 blocks). Only a relatively minor number of the cells were positive, and within the same case, there was considerable site-to-site variation in the number of positive cells. Large bizarre cells contained hCG/hCG-beta as well as the alpha subunit, if it was demonstrated in the same tumor as the beta subunit. Otherwise, the alpha subunit was found in small unremarkable cells. Giant cells that were smaller than those positive for hCG/hCG-beta contained in hPL. In some serial sections, hCG-alpha, hCG/hCG-beta, and hPL were segregated in different cell populations, supporting the concepts of their separate genetic control.

Development of Nongerm Cell Malignancies in Nonseminomatous Germ Cell Tumors

We report 2 cases of sarcomatous transformation of mixed germ cell tumors of the testis. Both patients received cisplatin-based combination chemotherapy. Embryonal rhabdomyosarcoma, chondrosarcoma and spindle cell sarcoma were the dominant pathological patterns in the metastatic sites. Nongerm cell malignancies in mixed germ cell tumors following chemotherapy may be more common than previously described.

The development of non-germ cell malignancies within germ cell tumors. A clinicopathologic study of 11 cases.

Eleven male patients had germ cell tumors of the testis (7), mediastinum (3), or retroperitoneum (1) in which non-germ cell malignancies developed. Such malignant non-germ cell elements were present in the primary excisions of five patients and were subsequently found in additional resected tissue in 10 of 11 patients. In the patients who had multiple pathology specimens examined, a progression from atypia to predominant non-germ cell malignancy was often found. The authors believe these malignant elements arose within teratomatous foci, since eight of nine cases had teratoma in the primary tumor, and teratoma was found in subsequently resected tissue in one additional case. Cisplatin therapy frequently "unmasked" the non-germ cell malignant elements by destroying the more chemosensitive germ cell cancers. The prognosis was worst for five patients who developed progressive embryonal rhabdomyosarcoma: two of these patients died of local spread of tumor, whereas a third died of metastatic sarcoma. Only one patient, who had total surgical excision of rhabdomyosarcoma, survived. Other forms of sarcoma that developed within germ cell tumors did not appear to adversely affect the prognosis beyond that of teratoma. It is currently recommended, when feasible, that patients with teratoma and sarcoma undergo total surgical excision. Further treatment with cisplatin regimens, after eradication of the germ cell component, has not been helpful. The role of other forms of chemotherapy remains speculative.

Clinicopathological features of retroperitoneal tumours.

The clinicopathological features of 49 neoplasms in the retroperitoneum, but not arising directly from a major retroperitoneal organ, are described. Abdominal pain and a mass, urinary tract symptoms and evidence of pressure on venous channels or nerves were common modes of presentation. In 6 cases the neoplasms were found incidentally and in 4 patients removal of the retroperitoneal mass was an elective procedure during the treatment of metastatic testicular germ cell tumour. Histopathological diagnosis revealed 4 major tumour types: germ cell neoplasms, non-germ cell metastatic carcinoma, soft tissue sarcoma and lymphoma. The differential diagnoses are discussed. A knowledge of the neoplasms to be expected in this site may indicate which pre-operative investigations should be undertaken.

Detection of an early pregnancy factor-like substance in sera of patients with testicular germ cell tumors.

Early pregnancy factor (EPF) is produced by both maternal and fetal tissue1,2 and has been detected previously only during pregnancy.3,4 The present report describes the detection of EPF, or an EPF-like substance (tEPF), in serum from patients with germ cell tumors of the testis. tEPF, or its free components, tEPF-A and tEPF-B, were detected in all 11 patients with nonseminomatous tumors and in 5 of 10 patients with seminoma. It was not detected in serum from healthy male controls nor in patients with non-germ cell tumors or benign testicular disease. It is suggested that tEPF may be an additional serum marker for germ cell tumors and may expand the group already detectable by such markers.

Endocrinology of testicular neoplasms

The hypothalamic-pituitary-testicular axis finely regulates levels of circulating sex steroids — especially testosterone and estradiol — and spermatogenesis. Testosterone, directly as an androgen and as a prehormone for estradiol, regulates LH secretion at both hypothalamic and pituitary levels. Leydig cells, principally under the control of LH, produce testosterone. Sertoli cells, under the control of FSH, and sensitive to intratesticular levels of testosterone, produce estradiol. This locally produced estrogen seems to be necessary for maturation of the germ cells. An abnormality in this sensitive control system, leading to elevations in gonadotrophins or steroid levels, may be etiologically important in both germ cell and nongerm cell neoplasia. Testicular cancers are associated frequently with endocrinologic manifestations, which may be more disabling to the patient than the malignant potential of the tumor, especially with childhood Leydig cell tumors. Estrogen dominance with an elevated estrogen/testosterone ratio can be seen in any testicular neoplasm and may result in gynecomastia. It may be due to a decrease in circulating testosterone or to an increase in estrogens. Virilization is seen frequently in Leydig cell tumors of adolescents. Further elucidation of hormonal interrelationships should lead to better understanding of the genesis of testicular neoplasia and to more effective therapy.

Alpha-fetoprotein, alpha-1-antitrypsin, and transferrin in gonadal yolk-sac tumours.

Since gonadal yolk-sac tumour in pure form or as a component of mixed germ cell tumour is in the majority of patients highly malignant, its histological recognition is of great prognostic importance. Yolk-sac tumour may assume various different histological guises, which have hitherto caused considerable terminological confusion; the present paper is aimed at correlating these morphological diversities with biochemical features which are consistent with yolk-sac differentiation. Using an enzyme-bridge immunoperoxidase technique, a series of 16 gonadal germ cell tumours with a yolk-sac component were screened for the presence of alpha-fetoprotein, alpha-1-antitrypsin, and transferrin. These proteins, normally produced by human yolk sac, were demonstrable in all the morphological patterns of yolk-sac tumour we have previously described. Six malignant non-germ cell tumours were submitted to the same investigations, and no evidence of the three protein markers was found in five; one tumour, however, an oat cell carcinoma of the bronchus, stained positively for transferrin.

Mn 2+-sensitive, soluble adenylate cyclase in rat testis Differentiation from other testicular nucleotide cyclases

In subcellular fractions prepared from homogenate of adult rat testis adenylate cyclase (ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1) activity was found in the particulate, primarily 600 × g for 10 rain, fractions, as well as in the cytosol. The properties of the adenylate cyclase in the cytosol differs substantially from the adenylate cyclase system associated with the 600 × g for 10 min particulate fraction. The cytosol enzyme, in contrast to the particulate adenylate cyclase, was found to be fluoride- and gonadotropin hormoneinsensitive. The cytosol adenylate cyclase appears to be located in the germ cell while the particulate enzyme system in the non-germ cell component of the seminiferous tubules. The cytosol adenylate cyclase was found to be distinct also from the guanylate cyclase present in the rat testis cytosol. The adenylate cyclase appears to be located in the germ cell component while the guanylate cyclase, in the non-germ cell tubular component. Furthermore, it was found that the cytosol guanylate cyclase develops at an earlier stage of spermatogenesis, and precedes the development of the cytosol adenylate cyclase.

The combined surgical and chemotherapeutic approach to non-seminomatous cancer of the testicle.

Of 250 testicular tumors treated up to May 1975 233 (93.2%) were germ cell and 17 (6.8%) non-germ cell tumors. Reexamining the histology of the last 123 patients only 29.3% had pure seminomas and 70.7% had non-seminomatous tumors. The results of regimens of combined surgical (extended semicastration and lymphadenectomy) and chemotherapeutic (triple-drug as well as Ifosfamid in combinations with low-dose radiafor stage II (37.5%) and stage II (16.7%). There were good results after 96 transperitoneal bilateral lymphadenectomies. But even in stages II and III results were achieved which would not have been possible without lymphadenectomy. It is pointed out that in the future, with improvements in cytostatic therapy, even better results including treatment of stage IV tumors can be expected.

Ovarian neoplasms in childhood and adolescence: II. Tumors of non-germ cell origin

Seventy-five (40 per cent) of primary ovarian neoplasms in patients under 20 years of age were considered to be of non-germ cell origin. The majority of lesions in this group (53) arose from the coelomic epithelium or its derivatives and all were unilateral. Thirty-four of these were of serous cell type and 19 were of mucinous cell type; none were of endometrial cell type. Although the youngest patient of this group was 11 years of age, no patient was premenarchial. Four cystadenomatous lesions were considered histologically to have malignant areas; 2 patients are alive and well 6 years and 18 months after diagnosis; one patient died of metastatic disease after 13 months and the fourth patient had metastases at the time of diagnosis and although no survival information is available must be presumed dead.Eight neoplasms were of nonspecialized gonadal stromal origin; 3 benign fibromas, 3 supportive tissue sarcomas, and 2 lymphoblastomas that were histologically identical with lesions of so-called African lymphoma.Fourteen neoplasms were derived from specialized gonadal stromal elements; 3 were granulosa cell tumors, 3 were thecomas, 2 were mixtures of granulosa and theca cells, 3 were Sertoli cell tumors, and 3 were Sertoli-Leydig cell tumors (arrhenoblastomas). None of the granulosa-theca cell group of neoplasms occurred before puberty. One granulosa cell tumor behaved in a malignant manner, metastasizing and causing death. The 3 Sertoli cell neoplasms occurred in girls 3, 7, and 8 years of age, and 2 were associated with precocious development. The 3 arrhenoblastomas, occurring after puberty, produced masculinizing effects. None of the Sertoli-Leydig cell groups of neoplasms behaved in a malignant manner.

Ovarian neoplasms in childhood and adolescence: I. Tumors of germ cell origin

Abstract Seventy-five (40 per cent) of primary ovarian neoplasms in patients under 20 years of age were considered to be of non-germ cell origin. The majority of lesions in this group (53) arose from the coelomic epithelium or its derivatives and all were unilateral. Thirty-four of these were of serous cell type and 19 were of mucinous cell type; none were of endometrial cell type. Although the youngest patient of this group was 11 years of age, no patient was premenarchial. Four cystadenomatous lesions were considered histologically to have malignant areas; 2 patients are alive and well 6 years and 18 months after diagnosis; one patient died of metastatic disease after 13 months and the fourth patient had metastases at the time of diagnosis and although no survival information is available must be presumed dead. Eight neoplasms were of nonspecialized gonadal stromal origin; 3 benign fibromas, 3 supportive tissue sarcomas, and 2 lymphoblastomas that were histologically identical with lesions of so-called African lymphoma. Fourteen neoplasms were derived from specialized gonadal stromal elements; 3 were granulosa cell tumors, 3 were thecomas, 2 were mixtures of granulosa and theca cells, 3 were Sertoli cell tumors, and 3 were Sertoli-Leydig cell tumors (arrhenoblastomas). None of the granulosa-theca cell group of neoplasms occurred before puberty. One granulosa cell tumor behaved in a malignant manner, metastasizing and causing death. The 3 Sertoli cell neoplasms occurred in girls 3, 7, and 8 years of age, and 2 were associated with precocious development. The 3 arrhenoblastomas, occurring after puberty, produced masculinizing effects. None of the Sertoli-Leydig cell groups of neoplasms behaved in a malignant manner.

TESTICULAR NEOPLASMS IN INFANTS AND CHILDREN. II. TUMORS OF NON-GERM CELL ORIGIN.

TESTICULAR NEOPLASMS IN INFANTS AND CHILDREN. II. TUMORS OF NON-GERM CELL ORIGIN.