Pulmonary metastasis: very late relapse of testicular embryonal carcinoma.

Testicular carcinoma recurrences represent a rare finding (1-6% in non-seminomatous germ cell tumours). However, cases of recurrence have been described many years later. We report a case of late recurrence of embryonic testicular carcinoma, after 26 years, with pulmonary metastases. Following evidence of increase of alpha-fetoprotein (AFP), the patient underwent a total body computed tomography scan that exhibited two pulmonary nodules, one in upper left lobe and other in left hilar region with multiple mediastinal and retrocrural lymph node enlargements All consolidations showed increased sugar uptake value at PET CT. Biopsies of lung consolidations confirmed diagnosis of recurrence of testicular carcinoma.

Treatment and Outcome of Patients with Stage IS Testicular Cancer: A Retrospective Study from the Spanish Germ Cell Cancer Group.

PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

A pipeline to quantify serum and cerebrospinal fluid microRNAs for diagnosis and detection of relapse in paediatric malignant germ-cell tumours.

BACKGROUND: The current biomarkers alpha-fetoprotein and human chorionic gonadotropin have limited sensitivity and specificity for diagnosing malignant germ-cell tumours (GCTs). MicroRNAs (miRNAs) from the miR-371-373 and miR-302/367 clusters are overexpressed in all malignant GCTs, and some of these miRNAs show elevated serum levels at diagnosis. Here, we developed a robust technical pipeline to quantify these miRNAs in the serum and cerebrospinal fluid (CSF). The pipeline was used in samples from a cohort of exclusively paediatric patients with gonadal and extragonadal malignant GCTs, compared with appropriate tumour and non-tumour control groups. METHODS: We developed a method for miRNA quantification that enabled sample adequacy assessment and reliable data normalisation. We performed qRT-PCR profiling for miR-371-373 and miR-302/367 cluster miRNAs in a total of 45 serum and CSF samples, obtained from 25 paediatric patients. RESULTS: The exogenous non-human spike-in cel-miR-39-3p and the endogenous housekeeper miR-30b-5p were optimal for obtaining robust serum and CSF qRT-PCR quantification. A four-serum miRNA panel (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p): (i) showed high sensitivity/specificity for diagnosing paediatric extracranial malignant GCT; (ii) allowed early detection of relapse of a testicular mixed malignant GCT; and (iii) distinguished intracranial malignant GCT from intracranial non-GCT tumours at diagnosis, using CSF and serum samples. CONCLUSIONS: The pipeline we have developed is robust, scalable and transferable. It potentially promises to improve clinical management of paediatric (and adult) malignant GCTs.

Cripto: Expression, epigenetic regulation and potential diagnostic use in testicular germ cell tumors.

Type II germ cell tumors arise after puberty from a germ cell that was incorrectly programmed during fetal life. Failure of testicular germ cells to properly differentiate can lead to the formation of germ cell neoplasia in situ of the testis; this precursor cell invariably gives rise to germ cell cancer after puberty. The Nodal co-receptor Cripto is expressed transiently during normal germ cell development and is ectopically expressed in non-seminomas that arise from germ cell neoplasia in situ, suggesting that its aberrant expression may underlie germ cell dysregulation and hence germ cell cancer. Here we investigated methylation of the Cripto promoter in mouse germ cells and human germ cell cancer and correlated this with the level of CRIPTO protein expression. We found hypomethylation of the CRIPTO promoter in undifferentiated fetal germ cells, embryonal carcinoma and seminomas, but hypermethylation in differentiated fetal germ cells and the differentiated types of non-seminomas. CRIPTO protein was strongly expressed in germ cell neoplasia in situ along with embryonal carcinoma, yolk sac tumor and seminomas. Further, cleaved CRIPTO was detected in media from seminoma and embryonal carcinoma cell lines, suggesting that cleaved CRIPTO may provide diagnostic indication of germ cell cancer. Accordingly, CRIPTO was detectable in serum from 6/15 patients with embryonal carcinoma, 5/15 patients with seminoma, 4/5 patients with germ cell neoplasia in situ cells only and in 1/15 control patients. These findings suggest that CRIPTO expression may be a useful serological marker for diagnostic and/or prognostic purposes during germ cell cancer management.

Mixed ovarian germ cell tumor composed of immature teratoma, yolk sac tumor and embryonal carcinoma.

We report the case of a 19-year-old woman experiencing lower abdominal distension and pain. Laboratory tests indicated elevated serum levels of Alpha-Fetoprotein (AFP) and human Chorionic Gonadotropin (hCG). A large mass was detected in the abdomen by physical examination and by transvaginal ultrasonography. Exploratory laparotomy was performed, and a smooth-surfaced, spherical, solid tumor was found on the left ovary, measuring 11.5 x 9.9 x 6.9 cm. Histological evaluation revealed that the tumor consisted of a combination of immature teratoma, Yolk Sac Tumor, and embryonal carcinoma; this is a very rare combination in mixed germ cell tumors.

Ovarian malignant mixed germ cell tumor with clear cell carcinoma in a postmenopausal woman.

Malignant germ cell tumors of the ovary are very rare and account for about 2-5% of all ovarian tumors of germ origin. Most patients are adolescent and young women, approximately two-thirds of them are under 20 years of age, occasionally in postmenopausal women. But clear cell carcinoma usually occurs in older patients (median age: 57-year old), and closely related with endometriosis. Here we report a case of a 55-year old woman with right ovarian mass that discovered by B ultrasonic. Her serum levels of human chorionic gonadotropin (hCG) and α-fetoprotein (AFP) were elevated. Pathological examination revealed the tumor to be a mixed germ cell tumor (yolk sac tumor, embryonal carcinoma and mature teratoma) with clear cell carcinoma in a background of endometriosis. Immunohistochemical staining showed SALL4 and PLAP were positive in germ cell tumor area, hCG, CD30 and OCT4 were positive in epithelial-like cells and giant synctiotrophoblastic cells, AFP, AAT, CD117 and Glyp3 were positive in yolk sac component, EMA and CK7 were positive in clear cell carcinoma, CD10 was positive in endometrial cells of endometriotic area. She was treated with surgery followed by seven courses of chemotherapy. She is well and serum levels of hCG and AFP have been decreased to normal levels.

Primary retroperitoneal lymph node dissection in low-stage testicular germ cell tumors: a detailed pathologic study with clinical outcome analysis with special emphasis on patients who did not receive adjuvant therapy.

OBJECTIVE: To evaluate, in detail, the histopathologic features of metastatic testicular germ cell tumors to retroperitoneal lymph nodes treated with primary retroperitoneal lymph node dissection (RPLND) and correlate the findings with patients' outcomes. MATERIALS AND METHODS: We studied 183 patients with documented pathologic stage II disease with or without elevated serum tumor markers, selected from 453 patients who underwent primary RPLND at our institution from 1989 to 2002. Tumor type(s), size and extent of disease, and amount of tumor necrosis were assessed and correlated with outcome. RESULTS: Embryonal carcinoma was the most common tumor type, present as the only component in 99 cases (54%) and the predominant tumor type (>50%) in 142 (78%). The number of positive lymph nodes ranged from 1 to 40 from a total of 2-80 lymph nodes examined (median, 28). Extranodal extension (ENE) was identified in 120 cases (66%). Among 73 patients followed up expectantly and with normal serum tumor markers, 19 experienced relapse, the probability of which was higher in patients with more positive nodes, larger metastases, and presence of ENE. However, none of these differences was statistically significant (all P >.2). The predominance of embryonal carcinoma and the presence of tumor necrosis were not significantly associated with outcome. CONCLUSION: In this cohort, most patients treated with primary RPLND and with positive lymph nodes also had ENE. We did not identify any variables to be significantly associated with relapse after RPLND in patients managed expectantly. Additional studies with more patients are needed to validate our findings.

A case of hereditary persistence of α-fetoprotein: diagnostic usefulness of the subfraction profile.

α-Fetoprotein is a well-established tumor marker for non-seminomatous germ cell tumors. Elevated α-fetoprotein levels, however, result from a variety of clinical conditions. Hereditary persistence of α-fetoprotein is a rare benign disorder in which serum α-fetoprotein levels are persistently elevated, but there are no disabilities and symptoms. A 35-year-old man was diagnosed with pT1 testicular embryonal carcinoma. Post-orchiectomy α-fetoprotein levels remained persistently elevated without clinical or radiographic abnormalities. His mother's elevated α-fetoprotein levels confirmed the diagnosis of hereditary persistence of α-fetoprotein. Lens culinaris agglutinin-reactive α-fetoprotein fractions have been reported as a useful diagnostic marker for non-seminomatous germ cell tumors; in this patient, its measurement showed high non-reactive α-fetoprotein levels, which indicated the low probability of residual tumors. The present case represents the third case of hereditary persistence of α-fetoprotein in Japan, and the first in which the α-fetoprotein subfraction was evaluated.

[Initial experience in laparoscopic retroperitoneal lymphadenectomy for the management of nonseminomatous testicular cancer]. / Experiencia inicial en linfadenectomía retroperitoneallaparoscópica para el manejo del cáncerde testículo no seminoma.

BACKGROUND: Germ cell tumors of the testis represent 1% of all cancers in males. The mean age of occurrence is between 15 and 35 years. Early diagnosis and accuracy of staging are factors that have an impact in survival. According with stage I SO in nonseminoma tumors, there are three management options. Choice among them is based on the risk of recurrence, their morbidity and informed consent of the patient. The objective of this paper is to present the first results of retroperitoneal laparoscopic lymphadenectomy (RLL) in testicular germ cell nonseminoma tumors stage I S-0 at the Oncology Unit of Hospital Juarez de México. METHODS: Retrospective study of the data base of patients diagnosed with nonseminomatous testicular cancer Stage I, S-0 and subject to retroperitoneal laparoscopic lymphadenectomy in the period between May 2010 to December 2011. RESULTS: Ten patients underwent transperitoneal retroperitoneal laparoscopic lymphadenectomy with modified limits, ipsilateral to the affected testicle, 70% were stage I-A, showing a nodal count of 15.3 nodes. None suffered from metastases. The followup mean for all patients was 9.6 months. One patient suffered retroperitoneal relapse off lymphadenectomy's reach 10 months after the original surgery. CONCLUSION: Retroperitoneal laparoscopic lymphadenectomy is a safe procedure with reasonable morbidity, hospital stay and nodal count. It requires a surgeon expert in laparoscopic techniques.

Des-gamma-carboxy prothrombin (PIVKA-II)-producing mediastinal embryonal carcinoma with features of hepatoid differentiation.

The case of a 48-year-old man with primary nonseminomatous embryonal carcinoma at the posterior mediastinum is described. The patient displayed extremely high plasma levels of Des-gamma-carboxy prothrombin (PIVKA-II) (4040 mAU/ml). Ultrasonography and dynamic computed tomography ruled out hepatocellular carcinoma (HCC) or liver metastasis. After preoperative systemic chemotherapy, total tumor resection was performed. Postoperatively, the plasma levels of PIVKA-II returned to within the normal range (24 mAU/ml). An immnohistochemical study using anti-PIVKA-II monoclonal antibody revealed the cytoplasmic expression of PIVK4-II in the carcinoma cells. These results indicate that tumor cells, which are manifested as hepatoid differentiation, may produce PIVKA-II. This case seems to be the first case reported in which PIVKA-II was produced by nonseminomatous mediastinal embryonal carcinoma without HCC or liver metastasis.

Clinical use of serum TRA-1-60 as tumor marker in patients with germ cell cancer.

TRA-1-60 antigen has been related to the presence of embryonal germ cell carcinoma (EC) and carcinoma in situ. Our study further investigated the clinical efficacy of TRA-1-60 as a serum tumor marker for germ cell cancer in the testis. Three groups of patients with germ cell tumors were included: Group 1, 34 patients with disseminated disease (24 nonseminomatous germ cell tumors [NSGCT] and 10 seminomatous germ cell tumors [SGCT]); this group of patients were followed during the course of chemotherapy with measurements of TRA-1-60, HCG and AFP; Group 2, 28 patients with Stage I NSGCT (22 with embryonal carcinoma [EC]-component and 6 without EC-component, median follow-up 15 months); and Group 3, 40 patients with Stage I pure SGCT (median follow-up 15 months). Seventy-eight percent of patients with disseminated EC-positive NSGCT had increased levels of TRA-1-60 before chemotherapy. After chemotherapy, levels of TRA-1-60 had dropped significantly (p < 0.01). Levels of TRA-1-60 did not normalize in 15% of NSGCT and 30% of SGCT patients after chemotherapy. This was not associated with recurrent disease. Approximately one-third of patients with Stage I NSGCT had increased values of TRA-1-60 during follow-up without having a relapse. Contrary to earlier reports TRA-1-60 is not at present useful as a tumor marker in patients with germ cell tumors. Although detecting a few early relapses the rate of false positive elevations in the tumor marker makes it unreliable in the clinical setting. Our study did confirm that elevated levels of TRA-1-60 were present in approximately 80% of patients with disseminated EC-positive NSGCT before start of chemotherapy and chemotherapy induced a significant decrease in levels of TRA-1-60. Thus, the TRA-1-60 antigen might still prove clinically useful provided that the reliability of the assay can be increased.

Detection of circulating testicular cancer cells in peripheral blood.

Patients who receive peripheral blood stem cell transplants are at risk of developing cancer recurrence due to the presence of malignant cells in the transplants. We investigated a sensitive method to detect malignant cells in the peripheral blood and peripheral blood stem cells of patients with testicular cancer using nested, reverse transcription-polymerase chain reaction (RT-PCR) to measure alpha-fetoprotein gene expression. Using this technique, a single cancer cell could be detected in 10(6) peripheral blood mononuclear cells. This is the first report of an attempt to detect circulating malignant cells in the peripheral blood of patients with testicular cancer by nested RT-PCR.

CA19-9: a possible serum marker for embryonal carcinoma.

We determined whether a carbohydrate antigen in serum, CA19-9, serves as a marker for embryonal carcinoma. Serum CA19-9 was serially measured in 18 male patients with a germ cell tumor. Five of 8 patients with an embryonal carcinoma had an elevated serum CA19-9. The elevated serum CA19-9 returned to normal in parallel to the clinical response to the treatment. Patients with a seminoma had a normal serum CA19-9 irrespective of their tumor size. Paraffin-embedded specimens of germ cell tumors from 9 of the 18 patients and 10 other patients were stained with the monoclonal antibody against CA19-9. These immunohistochemical stainings showed that embryonal carcinomas and mature teratomas were consistently positive and seminomas were often faintly positive for CA19-9, whereas choriocarcinomas, yolk sac tumors and immature teratomas were negative for CA19-9. These results indicate that serum CA19-9 may be a useful serum marker for embryonal carcinomas.

[Pure embryonal carcinoma of the ovary. A review of the literature apropos of a case]. / Carcinome embryonnaire pur de l'ovaire. Revue de la littérature à propos d'un cas.

A 25-year-old woman with a stage IA pure embryonal carcinoma of the left ovary, without elevated serum markers namely AFP and HCG (nor-positive immuno-histologic marking at the later pathological analysis) underwent surgery alone (unilateral salpingo-oophorectomy). She relapsed seven weeks later with peritoneal carcinomatosis. She still did not have elevated tumor markers. She then received five courses of a cis platinum-based chemotherapy (bleomycin, etoposide and cisplatinum, BEP) and achieved pathological complete response (as attested by a coelioscopic third look). This response is still lasting, fourteen months after the end of the procedure. Malignant ovarian germ cells tumors account for 2 to 5% of all ovarian cancers and embryonal carcinoma is rare. It may be associated with high serum levels of AFP and/or HCG, but not when the embryonal carcinoma is really pure. These markers are very helpful for patient follow-up but not in our patient's history. These tumors offer a very good chemosensitivity especially when treated with cisplatinum. This treatment dramatically improved their prognosis and extensive debulking surgery is yet unnecessary. Some questions still remains is there any specificity for embryonal carcinoma within malignant germ cell tumors of the ovary group? What is the best treatment for stage IA disease? When is a surgical second look (or a third look as for our patient) justified?

CD30 antigen in embryonal carcinoma and embryogenesis and release of the soluble molecule.

The expression, serological detection, and possible functional role of the CD30 antigen in Hodgkin's disease and anaplastic large cell lymphoma is well documented. In embryonal carcinoma (EC), the expression of this cytokine receptor has been demonstrated only by immunohistology. Because the CD30 monoclonal antibody Ki-1 was found to cross-react with an unrelated molecule, we examined by in situ hybridization testicular germ cell neoplasms for the presence of CD30-specific transcripts. CD30 mRNA was detectable in the tumor cells of 9 of 9 cases of EC or mixed germ cell tumors with an EC component but in no other nonlymphoid tumors. Thus, the CD30 transcript expression pattern proved to be identical to the immunostaining pattern seen with the CD30-specific monoclonal antibody Ber-H2. By Northern blot analysis, CD30 transcripts could be demonstrated in the EC cell line Tera-2. Employing a highly sensitive second generation sandwich enzyme-linked immunosorbent assay, we could detect the soluble CD30 molecule in 8 of 8 sera from patients with a diagnosis of EC but not in 8 of 10 sera from patients with other testicular germ cell tumors. In fetal tissue, no CD30-expressing germ cells or epithelial cells could be observed. Thus, the cellularly expressed CD30 marker for testicular neoplasms of EC type. Moreover, the serum levels of soluble CD30 antigen seem to be a promising parameter for monitoring patients with EC.

Familial testicular carcinoma: in search of genetic triggers.

Two cases of testicular tumours in non-twin brothers of a cancer-prone family are described. Cytogenetic studies of these two patients and human leucocyte antigen (HLA) typing of the family failed to identify any genetic defects. The authors propose using linkage analysis for further genetic studies but would require additional families for this to be performed.