Testicular germ-cell tumors in childhood and adolescence

Summary Testicular germ-cell tumors are relatively rare in childhood and adolescence, accounting for only 3.9% of all neoplasms. However, they have become a model for curable cancer. Furthermore, most of them have accurate serum markers [beta-human chorionic gonadotropin and alpha-fetoprotein], which provide in clinical stage I disease after semicastration a wait and see program. MAHO 82, 88, and 92 were cooperative studies on the treatment of testicular germ-cell tumors in childhood and adolescence. Between 1982 and 1993, 137 patients were registered. In all, 76 patients suffered from yolk-sac tumors (YST); 30, from differentiated teratomas (TD); 29, from malignant teratomas of either intermediate (MTI), undifferentiated (MTU), or trophoblastic type (MTT); and 2, from seminomas. All patients received semicastration. Chemotherapy was given to 53 patients on the basis of disease stage and histology. Standard therapy consisted of four courses of vinblastine, bleomycin and cisplatin. However, if viable tumor was suspected after two courses, delayed laparotomy was performed (seven patients). If there was then complete tumor regression, standard therapy was continued (four patients). If there was an incomplete tumor response, the patients received as salvage therapy three courses of etoposide (VP-16), ifosfamide, and cisplatin (three patients). Among the patients with YST, 73 had stage I disease and 3, higher-stage disease; 1 of these died due to tumor progression. In all, 56 patients were followed according to the wait and see policy; 9 of these needed a delayed standard chemotherapy. The rate of no evidence of disease (NED) was 98%. Among the patients with TD, 30 had stage I disease. The NED rate was 100%. Among the patients with malignant teratomas (MTI, MTU, and MTT), 13 had stage I disease. The NED rate was 100%. Ten patients had stage II disease and received chemotherapy. The NED value was 100%. Six patients had stage III disease; three died. Altogether, 26 of 29 patients survived disease-free. In summary, the probability for the disease-free survival of all 137 patients suffering from testicular germ-cell tumors is 97% after a median observation period of 60 months.     

Genetic factors in malignant germ-cell tumors

Summary The etiology of germ-cell tumors is largely unknown. A history of undescended testis is the major known risk factor. Epidemiology studies have established the importance of (unknown) environmental factors probably operating very early in life. However, there are large differences in incidence in different populations and races. Familial cases and patients with bilateral cancer have been described, and the incidence is greatly increased in individuals with certain malformations of the urogenital system. The latter observations point to a genetic component in the disease's etiology. In most germ-cell tumors an isochromosome of the short arm of chromosome 12, i(12p), can be demonstrated. This highly characteristic cytogenetic aberration can be diagnostic of germ-cell tumors and may have prognostic importance. This article summarizes the current knowledge about and ongoing research on genes involved in the development of germ-cell tumors.     

Secondary surgery in advanced testicular germ-cell tumors

Twenty-four patients with residual tumor after intensive chemotherapy for advanced testicular germ-cell tumors were subjected to secondary surgery. Twenty patients had complete resection with the following distribution of histological types: 4 embryonal carcinoma, 9 mature teratoma and 7 fibrous tissue. Eighteen of these patients remain free of disease. Four patients had incomplete resection. Two of these patients with embryonal carcinoma died later despite further treatment; 2 patients with teratoma remain free of disease. Secondary surgery is recommended in cases where residual tumor is found after intensive chemotherapy and where tumor markers are not elevated.     

Rhabdomyosarcomas with intermediate-filament inclusions and features of rhabdoid tumors. Light microscopic and immunohistochemical study.

A group of 27 rhabdomyosarcomas (RMS) whose histology showed abundant cells containing cytoplasmic intermediate-filament globular inclusions resembling those seen in rhabdoid tumors has been identified among Inter-group Rhabdomyosarcoma Study (IRS) I-III patients (less than 1%). Their histologic subtype was embryonal RMS in 22 and alveolar RMS in 5. One-half of tumors occurred in deep muscles of the extremities, retroperitoneum, or in the pelvis. Immunohistochemical analysis of 12 cases showed the inclusions to be vimentin or desmin positive. Anti-muscle-specific actin antibodies were positive in the cytoplasm of 11 cases, but not in the site of the intermediate-filament inclusions. Seven poorly differentiated neoplasms closely resembled rhabdoid tumors and possessed large nucleoli in most cells along with cytoplasmic inclusions. In contrast to true rhabdoid tumors, their nuclear chromatin was usually coarse. Immunohistochemistry proved useful in distinguishing tumors with early myoblastic differentiation. A positive anti-desmin, when confined to the cytoplasmic inclusions only, should be complemented with other muscle-specific antibodies, especially anti-muscle actin to separate RMS from rhabdoid tumors. The statistical analysis was limited by the small number of cases, but there was no statistical difference in survival when this group of RMS was compared with 996 IRS-II patients as a whole. The distinction of RMS with abundant intermediate-filament inclusions from rhabdoid tumors is of clinical importance because patients with true rhabdoid tumors have a highly unfavorable prognosis.     

Differential diagnosis of genitourinary tumors using monoclonal antibodies to intermediate filament proteins

Definitive diagnosis of poorly differentiated and metastatic neoplasms may be impossible using conventional histologic criteria. Recent developments in cell biology and immunology now enable us to answer such difficult diagnostic problems. Several varieties of structural proteins can be identified in malignant cells using monoclonal antibodies. The composition of these proteins can yield information regarding the origin of a neoplasm. Intermediate filaments are one such family of structural proteins. By characterization of these proteins, using a panel of monoclonal antibodies, poorly differentiated tumors may be definitively classified as carcinomas, sarcomas, lymphomas, or neural tumors. This approach to tumor diagnosis is now applicable to difficult problems in clinical urology.     

Cellular calcium distribution in fetal bones studied with K-pyroantimonate

Summary The calcium distribution in cartilage and bone cells during beginning ossification of fetal mouse long bones was studied after fixation with 2% K-pyroantimonate in 1% osmium.In the developing periosteum, the future osteoblasts showed a sparse cation-antimonate precipitate over the cytoplasm. In young osteoblasts the precipitate was accumulated on the mitochondrial membranes and the plasmalemma. Both organelles were sharply outlined by precipitate in the mature osteoblasts at the onset of mineralization. X-Ray microprobe analysis of these organelles demonstrated the presence of both Sb and Ca. In the extracellular compartment, a collagen-associated precipitate with 50 to 60 nm periodicity appeared during osteoblastic differentiation. During the initial phase of matrix mineralization, a random gross precipitate appeared in the matrix and seemed to be accumulated by osmiophilic matrix vesicles while the collagen fibrils lost their precipitate. Subsequently, during the confluent phase of matrix mineralization, the precipitate rapidly disappeared from the cells, leaving them devoid of precipitate once they were surrounded by mineralized matrix. Similar changes were found in the chondrocytes of the growth plate, but cartilage collagen, unlike osteoid collagen, did not bind precipitate. The results indicate that both osteoblasts and calcifying cartilage cells bind calcium prior to matrix mineralization. Bone collagen has strong pyroantimonate binding capacity, but it is not directly involved with initial stages of matrix mineralization, which starts in close association with matrix vesicles.     

Status and prospects of the treatment of disseminated germ-cell tumors

Summary Clinical investigation into the treatment of metastatic germ-cell tumors (GCT) has been highly successful. Future progress will depend on innovative approaches to identifying and preventing late drug toxicity, improving therapy for poor-risk patients, finding new drugs and therapies, and incorporating the findings of basic research into the clinical setting. This progress requires continued exchange of information among clinicians and laboratory investigators interested in these fascinating tumors.Supported in part by National Cancer Institute grants (CA-05826, CA-08748) and contracts (NO1-CM-57043), and a Junior Faculty Clinical Fellowship awarded to Dr. Bosl by the American Cancer Society     

Biology of metastases and its clinical implications: testicular germ-cell tumors

Summary This article deals with observations of the clinical behavior of metastatic germ cell cancers of testicular origin. Therefore, when we speak of biology of metastases, we refer to that seen by the clinician as opposed to the laboratory scientist. First, we will review our experience with chemotherapy for metastatic disease. From this we can gain insight into risk factors for relapse and survival. Furthermore, we can infer there are fundamental differences in the biology of germ cell cancers of testicular origin as opposed to primary mediastinal or primary retroperitoneal origin. Some of these differences are further discussed. We also identify good risk parameters and suggest criteria for expectant or conservative management postchemotherapy instead of postchemotherapy surgical management. Second, the diversity of metastases as evidenced by a wide histologic spectrum, is discussed in clinical terms. Among topics discussed are non-germ-cell malignant elements found within metastatic germ cell tumors, and possible mechanisms for their emergence. Third, the increasing awareness of long delayed, late relapse and its relative refractoriness to chemotherapy gives further insight into the clinical biology of metastatic germ cell cancer. The multipotential nature of the germ cell results in a wide variety of metastatic subtypes, each with its own clinical behavior. Therefore, a variety of clinical management strategies may be required based upon these different clinical behaviors.     

Immunohistochemical study of placental alkaline phosphatase in primary intracranial germ-cell tumors

Indirect immunoperoxidase staining by the peroxidase-antiperoxidase (PAP) technique was carried out on 23 human primary intracranial germ-cell tumors (17 germinomas, one embryonal carcinoma, one yolk-sac tumor, three teratomas, and one teratoma with embryonal carcinoma) and on six human primary pineal non-germ-cell tumors (one pineocytoma, two pineoblastomas, two astrocytomas, and one glioblastoma multiforme). The technique used specific rabbit antisera against placental alkaline phosphatase (PLAP), alpha-fetoprotein (AFP), and human chorionic gonadotropin (HCG). Thirteen of 17 intracranial germinomas (76.5%) showed positive staining for PLAP mainly on the tumor cell membrane. In six primary intracranial non-seminomatous germ-cell tumors, there was weak positive staining indicating the presence of PLAP in only a few cells of one embryonal carcinoma, and in some glandular epithelial cells of one teratoma; this staining was limited to the cytoplasm. None of the other six primary pineal non-germ-cell tumors showed any positive PLAP reaction. From these results, PLAP was shown to be very useful in histopathology as a diagnostic tumor marker of intracranial germinoma. Positive AFP staining was seen in several yolk-sac tumor cells and a few embryonal carcinoma cells. However, no intracranial germinomas and non-germ-cell tumors of the pineal region showed positive reaction. As for HCG, only one suprasellar germinoma and one pineal embryonal carcinoma among 29 specimens contained a few positive-staining tumor cells.     

Marker-positive patients with germ-cell tumors: when is residual tumor resection useful?

Summary We analyzed 33 patients with disseminated germ cell tumors (GCT) who underwent residual tumor resection (RTR) during the period from 1991–1997. The patients were markerpositive prior to surgery were analyzed. The histopathological examination of the resected masses, the marker dynamics and the relapse-free respectively the progressionfree survival, were evaluated. The status differed at primary diagnosis: minimal disease n = 1, moderate disease n = 15, advanced disease n = 17. The patients received at average 8,5 cisplatin-containing cycles of polychemotherapy. Only 11 patients underwent surgery after first-line-chemotherapy. The remaining received second- or third-line-chemotherapy prior to surgery. In 12 of 31 evaluable patients, a durable CR was achieved. The median follow-up for this group is 30 months (2–58 months). The histopathologic examination of the resected specimen and the tumor marker level prior to RTR do not permit determination of prognostic outcome. After operation 44 % of the AFP-positive and 30 % of the β -HCG-positive patients had a durable remission. If tumor marker levels at time of RTR are within normal range, disease-free survival is 72 %; in case of elevated markers 39 % will survive. If intensive chemotherapy fails to normalize markers, RTR remains the only option to change the fatal course of the disease.      

Size and status of metastases after inductive chemotherapy of germ-cell tumors

Summary Secondary resection of metastases remaining after inductive chemotherapy of advanced germ-cell tumors has thus far been obligatory. The absence of malignant components in one-third of all residual tumors and the high risk of the operation have led several authors to reconsider the criteria for this approach. In a retrospective study of 153 cases (127 evaluable) we investigated the histology of the primary tumor and the size of the residual tumor with regard to residual histology and outcome. Patients were divided into the following three groups according to the histology of the primary tumor: group I, pure seminoma (16 patients); group II, nonseminoma without teratoma (32 patients); and group III, nonseminoma with teratoma (79 patients). Among the 16 purely seminomatous tumors, the residual masses ranged from 2 to 12 cm; 12 consisted of necrotic tissue only, 3 contained malignant germ-cell elements, and 1 contained adult teratoma. The residuals of primarily teratoma-free nonseminomas measured 2–16 cm; the smallest residual tumor containing active malignant elements measured 4 cm, and the diameter of the largest necrotic residue was 6 cm. Four residuals contained mature teratoma. The size of residuals from teratomatous primary tumors was 3–24 cm; the smallest malignant tumor measured 5 cm, and the diamter of the largest purely necrotic mass was 8 cm. According to our results, a secondary operation may be omitted if the residual mass of a primary seminoma is smaller than 5 cm or if that of a primary nonseminoma without teratoma is less than 3 cm in diameter. However, firm conclusions can be drawn only after these criteria have been confirmed by an ongoing multicenter trial.     

Mucinous carcinoid as an unusual manifestation of endodermal differentiation in ovarian yolk sac tumors

We present, for the first time, two yolk sac tumors (YST) in women 37 and 18 years of age, one with a typical parietovisceral pattern and the other with a glandular pattern, which were associated with extensive areas of mucinous carcinoid (MC). The tumor in the first case had numerous nodules of tubulopapillary YST that merged with well-differentiated MC. This patient responded well to chemotherapy. The tumor in the second case consisted of an AFP-positive glandular YST, with a glandulopapillary pattern closely resembling fetal lung type adenocarcinoma, coexisting with an AFP-negative, cytokeratin 20-positive, atypical MC; transitional areas between the two components were also seen. In the material from the recurrences and metastases; however, no YST was present, the atypical MC having become the predominant component including areas that had become carcinomatous. There was a poor response to various chemotherapeutic regimens. AFP levels became negative during the course of disease paralleling the disappearance of the YST component and the overgrowth of an increasingly anaplastic MC. The patient died 1 year after diagnosis. We think that, in these cases, MC represented an unusual form of endodermal differentiation of the YST. It is important to differentiate the yolk sac and carcinoid components due to their different responses to chemotherapy and to evaluate the possibility of mucinous carcinoid developing into a highly aggressive carcinoma.     

Recent advances in the understanding of the pathology of testicular germ-cell tumors

Summary Most testicular cancers probably arise in intratubular germ cells. This article proposes that tumorigenesis involves two steps: activation of the germ cells, which can result either in simple proliferation (intratubular atypia) or in parthenogenetic development (teratomas), and malignant transformation, either simultaneously (embryonal carcinoma) of later (tumors with restricted developmental potential). The embryonal carcinoma cells then may be able to differentiate into the other types of nonseminomatous tumors according to the traditional schema. This model implies that histologically similar tumors have different origins and destinies. The clinical implications are discussed briefly.     

Evolution and controversies in the management of low-stage nonseminomatous germ-cell tumors of the testis

Summary The results of changing treatment modalities in 690 consecutive patients with low stages nonseminomatous germ-cell tumors (NSGCT) of the testis were analyzed. Overall, 120 patients (17.4%) suffered relapses, and 25 (3.6%) died of cancer after a follow-up period ranging from 2 to 20 years. The indications for primary (nerve-sparing) retroperitoneal lymph-node dissection (RPLND) were gradually restricted from clinical stages I, IIA, and IIB to stages I and IIA with normal postorchiectomy markers only, but we recognize that the management of clinical stage I NSGCT of the testis remains controversial. All other patients may be treated with primary chemotherapy followed by nerve-sparing RPLND for any residual mass. Adjuvant chemotherapy is mandatory in pathological stage IIC disease, but this pathological category will disappear with adoption of the restrictions for primary nerve-sparing RPLND, and two courses of adjuvant chemotherapy are adequate treatment for patients with pathological stages IIA and IIB disease, who cannot be carefully followed.     

Combination chemotherapy with cisplatin and etoposide for malignant intracranial germ-cell tumors. An experimental and clinical study

Antitumor activity against intracranial malignant teratoma by combination chemotherapy with cisplatin and etoposide was evaluated in experimental and clinical studies. A human teratoma cell line (Tera 2) was exposed in vitro to cisplatin and/or etoposide, after which cell growth inhibition and alterations of deoxyribonucleic acid (DNA) histograms were observed. The results indicated that a synergistic cytotoxic effect was achieved by use of both agents in combination. Four cases of recurrent intracranial germ-cell tumor (three malignant teratomas and one germinoma) were treated with cisplatin and etoposide. With this combination therapy, regression of the tumor was observed in all four cases (three complete and one partial), for a total response rate of 100%. During a follow-up period of 9 to 22 months, no recurrence or progression has been noted in three of these cases.     

Malignant ovarian tumors in children

Malignant ovarian tumors in childhood, though uncommon, should be considered in any female child with an abdominal mass. The treatment is prompt, complete surgical removal if possible. These tumors vary greatly in their malignancy, but if removed before spread has taken place, the child's prognosis may be relatively good. Unfortunately, complete resection is frequently impossible. Radical surgery has no place in this disease, but radiotherapy and chemotherapy may give some palliation. Long-term favorable results are the exception as exemplified by a 73% mortality in the small series of 15 patients reviewed here.     

Stage II nonseminomatous germ-cell testicular tumors — the Indiana experience and risk-benefit analysis

Summary Controversy exists in the appropriate management of patients with nonseminomatous testicular cancer presenting as clinical stage B disease. Traditional treatment in the United States has included retroperitoneal lymph-node dissection (RPLND). Conversely, in Europe and other places some of these patients have been managed with primary chemotherapy. The experience with RPLND in clinical stage B disease at Indiana University from 1965 to 1989 was reviewed. A total of 174 patients were considered to be in clinical stage B prior to RPLND. After RPLND, 23% of these patients (n=41) were found to have pathological stage A disease. In all, 77% (n=133) were determined to be in pathological stage B. Of those pathological stage B patients who did not receive adjuvant chemotherapy, 65% were cured by RPLND alone. The pathological stage B patients who went on the receive postoperative adjuvant chemotherapy displayed an overall 14% chance of relapse. (Patients treated early in the series did not receive cisplatin-based chemotherapy.) The overall survival over the entire period was 96%. In the more modern era, during which cisplatin-based chemotherapy was available, the overall survival was 98%. RPLND is an effective procedure for the management of clinical stage B nonseminomatous testicular cancer. It provides excellent survival in patients found to have pathological stage B disease; additionally, it avoids the unnecessary toxicity of chemotherapy in the 23% of patients who in fact are in pathological stage A.     

Study of antibodies to adenoviruses in patients with tumors of the urogenital system

The presumable relationship between viruses and malignant disease has been studied. Approximately 4000 assays for antibodies to adenovirus were carried out with sera of patients with malignant and nonmalignant diseases of the urogenital organs and other organic diseases. The search was directed in the first place at antibodies to the early non-virion antigens of adenovirus-12 of oncogenic properties. On the evidence of the complement fixation reaction antibodies to adenoviruses were found to be less frequent in malignant tumors and in hypertrophy of the prostate than in the control group. Antibody to the non-virion antigen of adenoviruses was found in 53 per cent of patients with neoplastic diseases and prostatic hypertrophy, in 18 per cent of those with urogenital diseases other than tumors and in 4 per cent of those with other organic diseases. The results point to a possible role of adenoviruses in tumors of the urogenital organs.     

Laparoscopic and open retroperitoneal lymph-node dissection for clinical stage I nonseminomatous germ-cell testis tumors

BACKGROUND AND PURPOSE: Laparoscopic retroperitoneal lymph node dissection (L-RPLND) has been reported as efficacious for staging of the retroperitoneum in patients with stage I nonseminomatous germ-cell testis tumors (NSGCT). However, reports are limited to a few centers, and this procedure has yet to be widely accepted as an alternative to open retroperitoneal lymph node dissection (O-RPLND). Thus, we compared our contemporary open and laparoscopic experience with RPLND. PATIENTS AND METHODS: A retrospective chart review identified 28 patients who underwent either open (N = 6) or laparoscopic (N = 22) RPLND for clinical stage I NSGCT since 2000. Each patient received the appropriate modified template dissection. Perioperative demographic data, histologic nodal status, and recurrence data were evaluated. The mean follow-up was similar in the two groups. RESULTS: The mean operative time was not significantly different (313 minutes for L-RPLND v 284 minutes for O-RPLND). However, L-RPLND did have a significantly shorter hospitalization (1.2 v 8.5 days). Significantly more lymph nodes were removed with O-LPLND than with L-RPLND (mean 33 v 17). There was a single recurrence outside the modified template after both L-RPLND and O-RPLND and one within-the-template recurrence in the O-RPLND group. CONCLUSIONS: The L-RPLND is associated with less blood loss and a shorter hospital stay than O-RPLND, whereas the lymph-node yield of O-RPLND is greater. However, during the critical early follow-up period, the oncologic effectiveness and morbidity of L-RPLND for clinical stage I NSGCT appears similar to that of O-RPLND.