Serum alphafetoprotein (AFP) in diagnosis and management of endodermal sinus (yolk sac) tumor and mixed germ cell tumor of the ovary.

Serum AFP was determined serially by radioimmunoassay in 13 patients with ovarian germ cell tumors and in one patient with bilateral pure gonadoblastoma. There were 4 patients with pure dysgerminoma, one with pure endodermal sinus tumor (EST) and 8 with mixed germ cell tumors, all containing EST. The patients with dysgerminoma and gonadoblastoma had normal serum AFP at all times. All patients with tumors containing EST had raised serum AFP, although in most cases it was first determined between 1 and 3 weeks after operation and there was no evidence of metastases. Serum AFP became normal 5 to 7 weeks after operation and began to rise when disease recurred. Serum AFP determinations detected presence of recurrent disease long before it became detectable by other methods. Serum CEA was determined serially by radioimmunoassay in 8 of these patients, including 2 who dies with metastases, and was normal on all occasions.     

Yolk sac carcinoma (endodermal sinus tumor): ultrastructure and histogenesis of gonadal and extragonadal tumors in comparison with normal human yolk sac.

Human yolk sac carcinomas have been studied only twice with the electron microscope, and have never been compared at this level with normal human yolk sac. In the present study, the ultrastructural features of three primary ovarian yolk sac carcinomas, omental metastases from one of these, and a primary retroperitoneal yolk sac carcinoma in a male are reported, as are the ultrastructural findings in human yolk sac from normal 7- and 12-week gestations. The most prominent feature of the tumors is the presence of voluminous basement membrane material (the nature of which is confirmed by indirect enzyme-labeled antibody technique in one case) in both intra-and extracellular location, corresponding to the PAS-positive hyaline globules seen in these tumors by light microscopy. The tumor cells are also demonstrated to produce this material in tussue culture. Although basement membrane has not been described previously in normal human yolk sac at 8 and 10 weeks' gestation, it was present in the 7-week specimen which we studied, suggesting that its production may be a feature of only very young sac. Other ultrastructural findings are also similar in human yolk sac carcinoma, normal human yolk sac, and rodent yolk sac and yolk sac carcinomas. Thus, these studies confirm the suggested germ cell-derived yolk sac origin of the human tumor.     

The incidence of yolk sac tumor (endodermal sinus tumor) elements in germ cell tumors of the testis in adults.

The incidence of yolk sac tumor (endodermal sinus tumor) elements was studied in 147 germ cell neoplasms of the testis in adults observed over a 4 1/2-year period. Excluding 79 cases of pure seminoma, yolk sac tumor elements were found in 26 (38%) of 68 tumors; in 8 tumors the yolk sac tumor was the predominant element. Yolk sac tumor elements were found admixed with all other germ cell tumor elements. Tumors composed entirely of yolk sac tumor were not encountered. Fifteen (57%) of the 26 patients with tumors containing yolk sac tumor elements have died of their disease during the period under study, compared with 13 (31%) of the remaining 42 patients, suggesting that the prognosis of adults with testicular tumors containing yolk sac tumor elements is unfavorable. This is in contrast to the relatively good prognosis of infants and young children with testicular yolk sac tumor, and similar to the prognosis of female patients with ovarian yolk sac tumor. The results of the present study give further support to the view that yolk sac tumor (endodermal sinus tumor) is not adistinctive neoplasm of the infant's testis, but a germ cell neoplasm differentiating in the direction of yolk sac or vitelline structures, and occurring in the testis, ovary and extragonadal sites in common with other germ cell neoplasms.     

Anterior mediastinal endodermal sinus (yolk sac) tumor in a female infant

The first known case of primary anterior mediastinal endodermal sinus (yolk sac) tumor in a female patient, occurring in a 20-month-old infant, is reported. The child presented with cough, fever, and listlessness. Chest x-ray revealed a right anterior mediastinal mass. At thoracotomy a large anterior mediastinal tumor extending from the neck to the diaphragm was found, and was almost totally resected. Microscopically, the tumor displayed many of the histologic patterns observed in EST. Other neoplastic germ cell elements were not identified. The ultrastructural and immunohistochemical findings further confirmed the diagnosis. Serum alpha-fetoprotein (AFP) level, determined during surgery, was elevated to 65,200 ng/ml, whereas serum beta-human chorionic gonadotropin level was normal. Postoperatively, combination chemotherapy consisting of vinblastine, bleomycin, cisplatin, dactinomycin, cyclophosphamide, and doxorubicin was administered with a maintenance program. After 18 weeks on this regimen all the findings were normal, including serum AFP level. The child is well and disease-free 25 months after diagnosis.     

Primary endodermal sinus (yolk sac) tumour of the liver.

Primary endodermal sinus tumour of the liver is an extremely rare neoplasm. A 37-year-old man presented with a mass in the left lobe of the liver and a raised serum alpha-fetoprotein concentration. A left hepatic lobectomy was performed. Histological examination revealed an endodermal sinus tumour of the liver. There was no evidence of an extrahepatic primary source.     

Primary endodermal sinus (yolk sac) tumor of the liver. First reported case.

A primary endodermal sinus (yolk sac) tumor of the liver occurring in an 18-month-old boy is described. Although several examples of extragonadal endodermal sinus tumors have occurred in other sites, this is believed to be the first reported instance of origin in the liver. An additional important feature was the detection of alpha-fetoprotein in a preoperative serum sample. Although no metastases were identified at the time of celiotomy, widespread metastases developed, and he died 6 1/2 months after an extended right hepatectomy was performed. Neither triple chemotherapy nor radiation therapy appeared to deter progressive spread of the neoplasm, although the metastases exhibited some radiosensitivity.     

Alpha-1 antitrypsin (AAT) and alphafoetoprotein (AFP) in sera of patients with germ-cell neoplasms: value as tumour markers in patients with endodermal sinus tumour (yolk sac tumour).

Serum alphafoetoprotein (AFP) and serum alpha-1 antitrypsin (AAT) were determined in 24 patients with germ-cell neoplasms of the gonads and extragonadal sites and in two patients with hepatocellular carcinoma. In the majority of the patients serial determinations were performed. All seven patients with testicular seminoma and four patients without evidence of active disease had normal levels of serum AAT and AFP. The remaining 13 patients with germ-cell neoplasms had tumours containing endodermal sinus tumour (yolk-sac tumour) elemetns. All these 13 patients had elevated levels of serum AFP and the levels were high or very high in most cases. Nine of these 13 patients had raised serum AAT, although the elevation above normal levels was only slight in a number of cases. When serial determinations were performed serum AAT levels frequently followed the pattern of serum AFP levels, but the AAT levels were frequently within normal limits and therefore the interpretation of the results was difficult, and much less reliable as compared with those for serum AFP. The elevation of serum AAT levels following the recurrence of the tumour was found to occur much later and was much less marked than elevation of serum AFP, which occurred early, showed a large rise and was a reliable marker of tumour recurrence in patients with germ-cell neoplasms containing endodermal sinus tumour elements. It is therefore considered that, although there is good evidence that serum AAT is produced by endodermal sinus tumour elements, serum AAT is not a useful monitor of disease activity in these patients, especially when compared with serum AFP, the value of which is well recognized. Serum AAT may be a useful tumour marker in patients with hepatocellular carcinoma, and this aspect should be investigated further.     

Immunohistochemical localisation of alpha-fetoprotein (AFP) in germ cell tumours: evidence for AFP production by tissues different from endodermal sinus tumour

20 germ cell tumours have been studied with respect to the presence of alpha-fetoprotein (AFP), using the peroxidase-antiperoxidase (PAP) technique. 6 out of 20 tumours contained elements of endodermal sinus tumour (EST) and were AFP positive. 16 tumours were diagnosed either as pure embryonal carcinomas (6) or as mixed germ cell tumours, containing elements of embryonal carcinoma (10). In 3 of these 16 tumours AFP was localised definitely in the embryonal carcinoma cells; in an additional 6, AFP was also detected but it could not be decided whether AFP was present in embryonal carcinoma cells or in EST cells during early differentiation. In 2 of 7 immature teratomas, AFP was shown to be present in cylindric epithelia. All seminomas (4) studied were AFP-negative. These results show that AFP, which occurs regularly in EST, may also be present in embryonal carcinomas as well as in immature teratomas. Thus, it seems that the immunohistochemical demonstration of AFP by the PAP technique is a suitable method of identifying late stages of embryonal carcinoma or early stages of endodermal sinus tumour during the process of differentiation.     

Primary endodermal sinus (yolk sac) tumor of the anterior mediastinum: a report of a successfully treated eleven-year-old boy.

An asymptomatic 11-year-old Japanese boy with an endodermal sinus (yolk sac) tumor of the anterior mediastinum was successfully treated with cisplatinum-based combination chemotherapy and subsequent surgical excision. The patient is alive and in good health 60 months from diagnosis.     

The prognostic significance of endodermal sinus tumor histology among patients treated for stage III nonseminomatous germ cell tumors of the testes

A retrospective study was undertaken to determine the prognostic significance of endodermal sinus tumor (EST) elements in 56 patients with Stage III nonseminatous germ cell tumors of the testes (NSGCTT). The study patients were treated with conventional vinblastine, bleomycin and cisplatinum chemotherapy prior to our recognition of EST as a distinct entity. Twenty-one (37.5%) of the patients had EST elements in their tumors. Nineteen patients had EST in their primary testis tumor, whereas two had EST in metastatic sites only. Prognostic criteria (tumor volume, Dixon-Moore classification and chemotherapy vinblastin and bleomycin [VB] and VB plus cisplatin [VB + P] ) were similar in EST and non-EST patients. Long-term disease-free survival was significantly poorer for patients with Stage III NSGCTT containing EST (38%) compared with those not containing EST (71%) (P = 0.04). All 12 patients with small volume disease (III-B1-III-B2), independent of the presence of EST, are alive and free of disease for more than 2 years. Only 6 of 18 patients (33%) with advanced disease and EST are alive and free of disease, whereas 17 of 26 (65%) of patients with advanced disease not containing EST are alive and free of disease (P = 0.074). The addition of single agent bolus cisplatin to the treatment of patients with advanced disease achieved no improvement in survival. Endodermal sinus tumor must be included in future studies of advanced Stage III NSGCTT as an important prognostic variable.     

Endodermal sinus (yolk sac) tumor elements in testicular germ-cell tumors in adults: comparison of prospective and retrospective studies

The incidence of endodermal sinus tumor (EST) or yolk sac tumor (YST) elements has been studied in two series of testicular germ-cell neoplasms in adults. One series, consisting of 200 germ-cell neoplasms seen from 1053 through 1968, was studied retrospectively, and the other, consisting of 147 cases seen from May 1974 through February 1979, was studied prospectively. Excluding the cases of pure seminoma, EST(YST) elements were found in 21 (28.7%) of 73 cases in the retrospective series and in 27 (44.4%) of 61 cases in the prospective series. The EST(YST) elements were in all cases admixed with other neoplastic germ-cell elements and varied from microscopic foci to being the predominant element within a tumor. The EST(YST) elements were histologically similar to infantile EST(YST) and EST(YST) in other locations. Serum alphafetoprotein (AFP) was determined in the majority of patients in the prospective series, and there was good correlation between the presence of EST(YST) elements within the tumor and elevated levels of AFP. The results of the present study indicate that EST(YST) elements occur quite frequently in testicular germ-cell neoplasms in adults and provide an explanation for the raised levels of serum AFP found in many adults with testicular germ-cell tumors. The results emphasize the importance of a thorough and careful pathologic examination of testicular germ-cell tumors, and the value of AFP as a tumor marker in patients with EST(YST). The results also lend further support to the view that EST(YST) elements found in testicular germ-cell tumors in adults are homologous with infantile EST(YST) and that EST(YST) is a distinctive and specific type of germ-cell neoplasm and should be included as such in the classification of testicular tumors.     

Treatment outcome of patients with extragonadal nonseminomatous germ cell tumors: the Saitama Cancer Center experience

Background

Survival of patients with extragonadal nonseminomatous germ cell tumors remains inferior to that of patients with advanced testicular cancer, although treatment is often the same for both conditions. In addition, the prognosis for nonseminomatous tumors has been shown to be worse than for seminoma.

Methods

Thirteen patients with extragonadal nonseminomatous germ cell tumors were treated between 1998 and 2011; the primary tumors were located in the mediastinum in six and in the retroperitoneum in seven. At initial diagnosis seven patients had distant metastases. According to the IGCCC, eleven patients had poor prognosis and two were intermediate. All 13 patients received cisplatin or carboplatin-based chemotherapy as initial treatment. The patients were further treated by use of a multi-modal strategy which included high-dose chemotherapy, aggressive surgery, and early introduction of salvage regimens.

Results

Complete response was obtained for eight patients. Among these complete responders, one patient remained relapse-free after post-chemotherapy surgical excision of viable cancer tissue. In the course of the chemotherapy, four patients died from cancer progression and one patient died as a result of post-chemotherapeutic sepsis. The other eight patients were alive at the end of the observation period. At the last observation all surviving patients were without evidence of disease. Five-year overall survival for all 13 patients was 62 %, and 5-year cancer-specific survival was 68 %.

Conclusion

Our results indicate that even patients with far-advanced extragonadal nonseminomatous germ cell tumors can be cured by intensive chemotherapy plus surgery.     

Endodermal sinus tumor (yolk sac tumor)--report of 52 cases and review of the literature of 1224 cases

52 cases of endodermal sinus tumors (EST) are reported and 1224 cases from the Chinese and foreign literature are reviewed. This tumor, occurring usually in the gonads and rarely at extragonadal sites, comprised 10-17.1% of the former. It is located on or along the mid-line of the body including the orbit and other organs. In this paper, there are two cases with the tumor located at the orifice of urethra and one case between the pubic bone and the urinary bladder which has never been reported. EST often occurs in people under the age of 35. EST in the gonadal sites is divided into infant-childhood and adult groups. In the former group the prognosis is better than that of the adult group when the tumor is located in the testis as well as those in the vagina. There is sex and age difference for some EST in extragonadal sites. Those in the mediastinum almost always occur in young males. Diagnosis is easily made by pathology and by serum alpha-fetal protein (SAFP). Pathologically it is divided into two types: simple EST and EST element mixed with other germ cell tumors which give the same prognosis. The authors suggest that SAFP be done for any patients with teratomata in order to avoid misdiagnosis. SAFP is not only diagnostic but also prognostic by monitering postoperative course. EST is a highly malignant tumor, rapidly growing and poor in prognosis. Recent reports show that operated patients supplemented by chemotherapy give much better results than by radiotherapy.     

Structure of the sugar chain of alphafetoprotein purified from a human yolk sac tumor and its reactivity with concanavalin A

We have attempted to determine the carbohydrate moiety of human alphafetoprotein (AFP) produced by a yolk sac tumor. AFP was obtained from the cystic fluid of human yolk sac tumors grown in nude mice and was purified using an immunoadsorbent column coupled with monoclonal anti-AFP antibody. Then, the carbohydrate chain of the purified AFP was quantitatively released from the polypeptide chain. The resulting oligosaccharide was labeled and, by sequential exoglycosidase digestion in combination with methylation analysis and periodate oxidation, the structure was determined to be: Sia alpha 2----6Gal beta 1----4GlcNAc beta 1----2Man alpha 1----6 (GlcNAc beta 1----4) (Sia alpha 2----6Gal beta 1----4GlcNAc beta 1----2Man alpha 1----3) Man beta 1----4GlcNAc beta 1----4 (Fuc alpha 1----6) GlcNAcOT Compared with the known structure of the sugar, chain of human hepatic AFP, it was found that the sugar chain of yolk sac AFP contained an additional sugar, N-acetylglucosamine (bisect GlcNAc) linked to the beta-mannose. In the light of recent knowledge, this result indicates that the Concanavalin A (Con-A) binding site of the sugar chain is blocked by this GlcNAc in human yolk sac AFP. This fact forms the basis for the clinical use of the Con-A binding test to determine the origin of AFP in patients.     

Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis.

PURPOSE: Relapsed extragonadal germ cell tumors patients (EGGCT) are treated with identical salvage chemotherapy regimens, as are patients with metastatic testicular cancer. This investigation evaluates the results of second-line chemotherapy in nonseminomatous EGGCT and tries to identify prognostic factors for survival. PATIENTS AND METHODS: We conducted a retrospective review of 142 patients treated at eleven European and American centers between 1975 and 1996. All had received cisplatin-containing regimens as induction treatment. RESULTS: Twenty-seven of 142 patients (19%) were long-term disease-free, 11% with primary mediastinal and 30% of patients with primary retroperitoneal disease. Median follow-up since start of salvage treatment was 11 months (range, 1 to 157) for all patients and 45 months (range, 6 to 157) for surviving patients. Forty-eight patients (34%) received high dose chemotherapy with autologous bone marrow transplant at relapse, and 10 of these patients (21%) are continuously disease-free. Primary mediastinal location (P =.003), sensitivity to cisplatin (P =.003), elevated beta-HCG at relapse (P: =.04), and normal LDH at diagnosis (P =.01) were shown to be significant negative prognostic factors for overall survival in univariate; mediastinal location [relative risk ratios (HR) = 1.9; 95% confidence intervals (CI), 1.2 to 3.0] and sensitivity to cisplatin [HR = 2.4; 95% CI, 1.1 to 5.2] were significant negative prognostic factors in multivariate analysis. CONCLUSION: Although current salvage strategies will cure between 20% and 50% of recurrent metastatic testicular cancer, relapsed nonseminomatous EGGCT patients appear to have an inferior survival rate, in particular in case of primary mediastinal location. Mediastinal primary tumor and inadequate response to cisplatin-based induction chemotherapy have been identified as independent negative prognostic factors, both associated with an approximately two-fold higher risk for failure of salvage treatment.     

卵巢卵黄囊瘤的治疗及预后

背景与目的：探讨卵巢卵黄囊瘤的治疗方法与预后因素。方法：回顾性分析浙江省肿瘤医院1980年1月-2000年1月收治的卵巢卵黄囊瘤52例的临床病例资料。根据治疗方法将患者分为4组：A组（11例）行不保留生育功能手术加术后以铂类为主联合化疗；B组（10例）行不保留生育功能手术加术后以非铂类的联合化疗；C组（23例）行保留生育功能的分期手术加术后以铂类为主的联合化疗；D组（8例）行保留生育功能的分期手术加术后非铂类的联合化疗。对4组患者的生存率及预后因素进行分析。结果：52例患者5年生存率为69．2％。A组、B组、C组和D组的5年生存率分别为81．8％、40．0％、82．6％和50．0％。术后接受铂类为主化疗患者5年生存率为82．4％（28／34），显著高于非铂类化疗患者44．4％（8／18）（P〈0．05）。A组与B组、C组与D组比较，具有显著性差异（P〈0．05）。但A组与C组、B组与D组比较，无显著性差异（P〉0．05）。多因素分析显示，临床期别、术后残留病灶、术后以铂类为主的联合化疗是影响卵巢卵黄囊瘤患者预后的重要因素。结论：进行准确的手术分期和理想的减瘤术，术后辅以铂类为主的联合化疗，是卵巢卵黄囊瘤理想的治疗模式。保留生育功能手术不影响患者的预后。     

Serum tumor markers and patient allocation to good-risk and poor-risk clinical trials in patients with germ cell tumors.

The allocation of patients with advanced germ cell tumors (GCT) to different treatment programs based on clinical characteristics is standard in the design of clinical trials today. Studies have shown that substantial differences exist between entry criteria and that these differences could influence the outcome of clinical trials. The factors contributing to these differences are not clear due to patient selection biases. Two hundred five unselected and consecutive patients allocated to and treated in good-risk and poor-risk treatment programs at Memorial Sloan-Kettering Cancer Center (MSKCC) were reassigned risk status by the Indiana University (IU) Classification. The results were compared with those of the Southeastern Cancer Study Group (SECSG). The results using both criteria indicated substantial agreement in total end results and the identification of good-risk patients. The results in poor-risk patients differed substantially, with 39 patients (19%) classified as poor-risk by MSKCC criteria and 66 (32%) by Indiana criteria. The major discrepancy occurred in IU Stage 7, in which 26 of 32 patients (81%) achieved a complete response. The major factor contributing to this difference in risk assignment was the use of serum tumor markers. Serum tumor markers must be incorporated into risk assignment criteria for GCT clinical trials to minimize the number of good-risk GCT patients in poor-risk trials.     

SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors,with particular utility in detection of metastatic yolk sac tumors

BACKGROUND:

The correct diagnosis of metastatic germ cell tumors is critical, because these tumors can be effectively treated and are even cured with modern therapy. Their histopathologic diagnosis can be challenging without immunohistochemical markers, which currently have limitations. SALL4 is a novel stem cell marker essential to maintain pluripotency and self‐renewal of embryonic stem cells. In the current study, the authors investigated the utility of SALL4 as a potential diagnostic marker for metastatic germ cell tumors.

METHODS:

Ninety metastatic germ cell tumors from testis, ovary, and extragonadal sites were stained with a monoclonal SALL4 antibody. In addition, 170 metastatic nongerm cell malignancies, including 158 carcinomas (6 head and neck, 8 thyroid, 12 lung, 8 breast, 7 hepatocellular, 3 cholangiocarcinomas, 2 ampullary, 10 pancreatic, 18 gastric, 15 esophageal, 10 renal cell, 10 urothelial, 12 prostatic, 18 ovarian, 6 uterine, and 13 colonic) and 12 melanomas, were also stained to test SALL4 specificity.

RESULTS:

All 22 seminomas, 7 dysgerminomas, 22 embryonal carcinomas, and 14 of 15 yolk sac tumors displayed strong and diffuse SALL positivity in >90% of tumor cells (80% of tumor cells were strongly positive in the remaining yolk sac tumor). Five of 7 choriocarcinomas and 9 of 18 teratomas were also variably positive for SALL4. In contrast, only 10 (esophageal, gastric, and colonic adenocarcinomas) of 170 metastatic somatic tumors demonstrated focally weak SALL4 reactivity (<25% tumor cells).

CONCLUSIONS:

SALL4 is a novel sensitive and highly specific marker for metastatic germ cell tumors, and is particularly useful for detecting metastatic yolk sac tumors. Cancer 2009. © 2009 American Cancer Society.