Pure Embryonal Carcinoma Research Articles

MP10-10 OUTCOMES OF PROGRESSION ON SURVEILLANCE FOR CLINICAL STAGE I NONSEMINOMATOUS GERM CELL TUMOURS

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Penis/Testis/Urethra: Malignant Disease1 Apr 2015MP10-10 OUTCOMES OF PROGRESSION ON SURVEILLANCE FOR CLINICAL STAGE I NONSEMINOMATOUS GERM CELL TUMOURS Madhur Nayan, Michael A.S. Jewett, Lynn Anson-Cartwright, Philippe Bedard, Malcolm Moore, Peter Chung, Padraig Warde, Joan Sweet, Martin O'Malley, and Robert J. Hamilton Madhur NayanMadhur Nayan More articles by this author , Michael A.S. JewettMichael A.S. Jewett More articles by this author , Lynn Anson-CartwrightLynn Anson-Cartwright More articles by this author , Philippe BedardPhilippe Bedard More articles by this author , Malcolm MooreMalcolm Moore More articles by this author , Peter ChungPeter Chung More articles by this author , Padraig WardePadraig Warde More articles by this author , Joan SweetJoan Sweet More articles by this author , Martin O'MalleyMartin O'Malley More articles by this author , and Robert J. HamiltonRobert J. Hamilton More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.411AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Active surveillance (AS) is universally accepted for clinical stage (CS) IA non-seminoma germ cell tumours (NSGCT) and favoured by most centers for CSIB NSGCT. Patients progressing on AS are typically treated with chemotherapy, but there is no consensus. We describe patterns and mode of detection of progression and treatment of progression in our NSGCT AS cohort. METHODS From December 1980 to August 2011, 466 CSI NSGCT patients were managed with AS and 133 (28%) had disease progression while on AS. Treatment upon progression was physician choice but based on site of progression (e.g. retroperitoneum vs. extra-retroperitoneal), size or multifocality, and markers (S0 or stable, low level S1 vs. ≥ S1). Mode of detection of progression, characteristics at progression and primary treatment of progression (chemotherapy vs. retroperitoneal lymphadenectomy (RPLND)) were explored. Multivariate logistic regression was used to explore factors associated with receipt of more than one therapy in treatment of progression after surveillance. RESULTS Median time to progression was 7.3 months and detected by routine imaging (47%), routine serum tumour markers (37%), or both (12%). Progression most frequently occurred in the retroperitoneum (67%). Following progression, first-line treatment was chemotherapy for 71 (53%), RPLND for 51 (38%) and 11 (8.3%) underwent other therapy. In 59%, only one modality of treatment was required: chemotherapy only in 42/71 (59%); RPLND only in 36/51 (71%). For those treated with chemotherapy, pure embryonal carcinoma in the orchiectomy pathology (OR 0.11; p=0.05) was inversely associated with requiring further therapy. For those treated with RPLND, elevated markers pre-RPLND (OR 7.31; p=0.01) was associated with requiring further therapy. Overall, a second relapse occurred in 25/133 (19%) patients. With a median follow-up of 8.2 years, there were 5 deaths from testis cancer (3.8% of AS progressors; only 1.1% of overall AS cohort). CONCLUSIONS The majority of patients progressing on surveillance do so in the retroperitoneum and within the first year. Of those that progress, most will achieve complete response with single modality treatment. In particular, RPLND can be utilized as monotherapy in select cases. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e114-e115 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Madhur Nayan More articles by this author Michael A.S. Jewett More articles by this author Lynn Anson-Cartwright More articles by this author Philippe Bedard More articles by this author Malcolm Moore More articles by this author Peter Chung More articles by this author Padraig Warde More articles by this author Joan Sweet More articles by this author Martin O'Malley More articles by this author Robert J. Hamilton More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Outcomes of progression on surveillance for clinical stage I nonseminomatous germ cell tumours (NSGCT).

377 Background: Active surveillance (AS) is universally accepted for clinical stage (CS) IA and favoured by most centers for CSIB. Patients progressing on AS are typically treated with chemotherapy, but there is no consensus. We describe patterns and mode of detection of progression and treatment of progression in our NSGCT AS cohort. Methods: From Dec 1980 to Aug 2011, 466 CSI NSGCT patients were managed with AS and 133 (28%) had disease progression while on AS. Treatment upon progression was physician choice but based on site of progression (e.g. retroperitoneum vs. extra-retroperitoneal), size or multifocality, and markers (S0 or stable, low level S1 vs. ≥ S1). Mode of detection of progression, characteristics at progression and primary treatment of progression (chemotherapy vs. retroperitoneal lymphadenectomy (RPLND)) were explored. Multivariate logistic regression was used to explore factors associated with receipt of more than one therapy in treatment of progression after surveillance. Results: Median time to progression was 7.3 months and detected by routine imaging (47%), routine serum tumour markers (37%), or both (12%). Progression most frequently occurred in the retroperitoneum (67%). Following progression, first-line treatment was chemotherapy for 71 (53%), RPLND for 51 (38%) and 11 (8.3%) underwent other therapy. In 59%, only one modality of treatment was required: chemotherapy only in 42/71 (59%); RPLND only in 36/51 (71%). For those treated with chemotherapy, pure embryonal carcinoma in the orchiectomy pathology (OR 0.11; p=0.05) was inversely associated with requiring further therapy. For those treated with RPLND, elevated markers pre-RPLND (OR 7.31; p=0.01) was associated with requiring further therapy. Overall, a second relapse occurred in 25/133 (19%) patients. With a median follow-up of 8.2 years, there were 5 deaths from testis cancer (3.8% of AS progressors; only 1.1% of overall AS cohort). Conclusions: The majority of patients progressing on surveillance do so in the retroperitoneum and within the first year. Of those that progress, most will achieve complete response with single modality treatment. In particular, RPLND can be utilized as monotherapy in select cases.

Pure embryonal carcinoma of testis presenting with extensive metastasis

Embryonal carcinoma is a type of non-seminomatous germ cell tumor. Pure embryonal carcinoma of testis occurs only in 3–4% cases. We present a case of 34-year-old man with aggressive clinical course. At the time of presentation, he had left testicular swelling along with supraclavicular mass with extensive metastasis to retroperitoneum, liver, and lung. On gross pathological examination, specimen showed tumor replacing entire testis with involvement of rete testis, epididymis, and spermatic cord. It is observed that many patients with a tumor composed predominantly of embryonal carcinoma have metastasis at the time of diagnosis. Embryonal carcinoma is an aggressive tumor due to its tendency to early hematogenous spread emphasizing its need for early detection and treatment. The estimation of serum tumor marker levels is not conclusive in these cases. We are presenting this case for its rarity, and advanced stage of disease with clinical and histomorphological features.

Role of SOX2 in the Etiology of Embryonal Carcinoma, Based on Analysis of the NCCIT and NT2 Cell Lines

The transcription factor SOX2, associated with amongst others OCT3/4, is essential for maintenance of pluripotency and self-renewal of embryonic stem cells. SOX2 is highly expressed in embryonal carcinoma (EC), the stem cell component of malignant nonseminomatous germ cell tumors, referred to as germ cell cancer (GCC). In fact, OCT3/4 together with SOX2 is an informative diagnostic tool for EC in a clinical setting. Several studies support the hypothesis that SOX2 is a relevant oncogenic factor in various cancers and recently, SOX2 has been suggested as a putative therapeutic target for early stage EC. We demonstrate the presence of genomic amplification of SOX2 in an EC cell line, NCCIT, using array comparative genome hybridization and fluorescence in situ hybridization. Down-regulation of SOX2 by targeted siRNA provokes NCCIT cells towards apoptosis, while inhibition of OCT3/4 expression induced differentiation, with retained SOX2 levels. Mice pluripotent xenografts from NCCIT (N-NCCIT and N2-NCCIT) show a consistent SOX2 expression, in spite of loss of the expression of OCT3/4, and differentiation, with retained presence of genomic amplification. No SOX2 amplification has been identified in primary pure and mixed EC in vivo patient samples so far. The data presented in this study are based on a single EC cell line with a SOX2 amplification, with NT2 as control EC cell line, showing no profound induction of apoptosis upon SOX2 downregulation. The findings are of relevance to identify mechanisms involved in the pathogenesis of EC tumors, and support the model of SOX2-oncogene dependency of EC, which however, does not exclude induction of differentiation. This finding is likely related to the presence of wild type p53 in GCC, resulting in expression of downstream target genes, amongst others miR-34a, miR-145 and SOX2, associated to the unique sensitivity of GCC to DNA damaging agents.

Persistent CD30 Expression by Embryonal Carcinoma in the Treatment Time Course: Prognostic Significance of a Worthwhile Target for Personalized Treatment

CD30 is expressed by untreated embryonal carcinoma, supporting the rationale for a targeted approach. However, the reported chemotherapy induced switching off of CD30 noted on immunohistochemistry may affect its therapeutic potential for disease relapse. We evaluated persistent CD30 expression and its prognostic meaning in cases of post-chemotherapy residual disease. Paraffin blocks of surgical samples that yielded nonteratomatous viable cells after 1 or more cisplatin based chemotherapy treatments were retrieved and reassessed by 2 pathologists blinded to the study purpose. Multivariable analysis was done for prespecified factors. A total of 49 cases of pure embryonal carcinoma or mixed germ cell tumor from August 1991 to August 2012 had full clinical data and suitable tissue available for analysis. Of the 35 cases (71.4%, 95% CI 56.7-83.4) with preserved CD30 positivity 14 (40.0%) showed residual disease after a median of 1 regimen (IQR 1-2). Five-year overall survival in CD30 positive and negative cases was 37.0% (95% CI 22.1-61.8) and 50.1% (95% CI 27.9-90.0, p=0.078), while after first line treatment it was 23.2% (95% CI 8.6-62.5) and 47.6% (95% CI 18.8-100, p=0.025), respectively. On multivariable analysis CD30 positivity was a significant prognostic factor for progression-free survival (HR 2.32, 95% CI 1.04-5.19) and overall survival (HR 2.77, 95% CI 1.05-7.29). CD30 was retained even after an intensive pretreatment load, confirming that it is a reliable treatment target. Its expression was associated with a significantly poorer prognosis in multiple relapse/chemoresistant cases and it was an independent prognostic factor for survival.

Persistence of CD30 expression by embryonal carcinoma (EC) in the treatment time course: A retrospective series of multirelapsing germ cell tumors (GCT).

329 Background: CD30 is invariably expressed by untreated EC thus lending support to a rationale for a targeted approach. However, preliminary reports claimed an effect of chemotherapy (CT)-induced downmodulation of CD30 that might affect the potential use in relapsing disease. We aimed at evaluating the persistence of CD30-positivity in post-CT residuals. Methods: We retrieved paraffin-embedded post-CT samples yielding non-teratoma viable cells after ≥ 1 CDDP-based CT from the institutional surgical series. EC component was required and assessed by morphology and Oct-3/4 staining. The entire set was re-stained for CD30 and assessed by 2 pathologists blinded to study purpose. CD30-positivity was defined as a >80% membranous staining with a diffuse moderate-to-strong intensity. Clinical data included site of tumor primary, histology, CT regimen, and type of surgery. Results: From 12/1990 to 09/2012, a total of 246 cases with pure EC or mixed GCT residuals were treated. 49 (EC: 16; mixed GCT: 33) had both complete data and suitable tissue for study purposes. 40 pts had retroperitoneal or mediastinal nodes, 12 pts had lung metastases, 4 had either liver, bone or brain mets. 35/49 cases (70%) preserved CD30 positivity. 20/35 (57%) pts had residual disease after 1stline CT, 15/35 (43%) after multiple CTs (median 3.5, range 2-5). 2 pts (6%) had undergone high-dose CT and 4/35 (11%) were late relapses. 32/35 pts (91%) had gonadal primary, 1 had a retroperitoneal and another a mediastinal primary. The median survival of 35 CD30-positive patients was 16 mos (IQR 3.3-22.9) while it was 48.5 mos (IQR 21.7-72.6) for the 14 CD30-negative patients (p=0.0297 at Gehan-Breslow-Wilcoxon test). 5-year overall survival of CD30-positive and negative patients was 35.7% (95% CI: 18.2-53.6) and 49.7% (95% CI: 19.7-74.0), respectively. Conclusions: Our results on selected relapsing pts suggest that EC retained CD30 even in the far salvage setting, thus confirming to be a reliable target for treatment. A trend towards a poorer prognosis and shorter survival characterized CD30+ cases. A phase 2 study with the antibody-drug conjugate Brentuximab vedotin is currently in plan for GCT.

TRA-1-60+, SSEA-4+, POU5F1+, SOX2+, NANOG+ Clones of Pluripotent Stem Cells in the Embryonal Carcinomas of the Testes

Cancer of the testes is currently the most frequent neoplasm and a leading cause of morbidity in men 15-35 years of age. Its incidence is increasing. Embryonal carcinoma is its most malignant form, which either may be resistant or may develop resistance to therapies, which results in relapses. Cancer stem cells are hypothesized to be drivers of these phenomena. The specific aim of this work was identification and isolation of spectra of single, living cancer stem cells, which were acquired directly from the patients' biopsies, followed by testing of their pluripotency. Biopsies were obtained from the patients with the clinical and histological diagnoses of the primary, pure embryonal carcinomas of the testes. The magnetic and fluorescent antibodies were genetically engineered. The SSEA-4 and TRA-1-60 cell surface display was analyzed by multiphoton fluorescence spectroscopy (MPFS), flow cytometry (FCM), immunoblotting (IB), nuclear magnetic resonance spectroscopy (NMRS), energy dispersive x-ray spectroscopy (EDXS), and total reflection x-ray spectroscopy (TRXFS). The single, living cells were isolated by magnetic or fluorescent sorting followed by their clonal expansion. The OCT4A, SOX2, and NANOG genes' transcripts were analyzed by qRTPCR and the products by IB and MPFS. The clones of cells, with the strong surface display of TRA-1-60 and SSEA-4, were identified and isolated directly from the biopsies acquired from the patients diagnosed with the pure embryonal carcinomas of the testes. These cells demonstrated high levels of transcription and translation of the pluripotency genes: OCT4A, SOX2, and NANOG. They formed embryoid bodies, which differentiated into ectoderm, mesoderm, and endoderm. In the pure embryonal carcinomas of the testes, acquired directly from the patients, we identified, isolated with high viability and selectivity, and profiled the clones of the pluripotent stem cells. These results may help in explaining therapy-resistance and relapses of these neoplasms, as well as, in designing targeted, personalized therapy.

TRA-1-60+, SSEA-4+, Oct4A+, Nanog+ Clones of Pluripotent Stem Cells in the Embryonal Carcinomas of the Ovaries

Embryonal carcinoma of the ovary (ECO), pure or admixed to other tumors, is the deadly gynecological cancer. The specific aim of this work was identification, isolation, clonal expansion, and molecular profiling of the pluripotent cells in the embryonal carcinomas of the ovaries. The samples were acquired from the patients, who were clinically and histopathologically diagnosed with the advanced, pure embryonal carcinomas of the ovaries. The cell surface display of the TRA-1-60 and SSEA-4 was analyzed by flow cytometry (FCM), immunoblotting (IB), multiphoton fluorescence spectroscopy (MPFS), nuclear magnetic resonance spectroscopy (NMRS), and total reflection x-ray spectroscopy (TRXFS). The transcripts of the Oct4A and Nanog were analyzed by qRTPCR and MPFS and the products by MPFS. The human pluripotent, embryonic stem cells (ESC), human pluripotent, embryonal carcinoma of the testes (ECT), healthy tissues of the ovary (HTO), healthy tissue of testes (HTT), peripheral blood mononuclear cells (PBMC), and bone marrow mononuclear cells (BMMC) served as the controls. The studied embryonal carcinomas of the ovaries (ECOs) contained the cells with the strong surface display of the TRA-1-60 and SSEA-4, which was similar to the pluripotent ESC and ECT. Their morphology was consistent with the histopathological diagnosis. Moreover, these cells showed strong expression of the Oct4A and Nanog, which was similar to the pluripotent ESC and ECT. The ECO cells formed embryoid bodies, which differentiated into ectoderm, mesoderm, and endoderm. These cells were induced to differentiate into muscles, epithelia, and neurons. Herein, we revealed presence and identified molecular profiles of the clones of the pluripotent stem cells in the embryonal carcinomas of the ovaries. These results should help us with refining molecular diagnoses of these deadly neoplasms and design biomarker-targeted, patient-centered, personalized therapy.

Protocol for the Examination of Specimens From Pediatric and Adult Patients With Extragonadal Germ Cell Tumors

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the ‘‘Surgical Pathology Cancer Case Summary (Checklist)’’ portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.

Non–Risk-Adapted Surveillance in Clinical Stage I Nonseminomatous Germ Cell Tumors: The Princess Margaret Hospital’s Experience

BackgroundSince 1981 Princess Margaret Hospital has used initial active surveillance (AS) with delayed treatment at relapse as the preferred management for all patients with clinical stage I nonseminomatous germ cell tumors (NSGCT). ObjectiveOur aim was to report our overall AS experience and compare outcomes over different periods using this non–risk-adapted approach. Design, setting, and participantsThree hundred and seventy-one patients with stage I NSGCT were managed by AS from 1981 to 2005. For analysis by time period, patients were divided into two cohorts by diagnosis date: initial cohort, 1981–1992 (n=157), and recent cohort, 1993–2005 (n=214). InterventionPatients were followed at regular intervals, and treatment was only given for relapse. MeasurementsRecurrence rates, time to relapse, risk factors for recurrence, disease-specific survival, and overall survival were determined. Results and limitationsWith a median follow-up of 6.3 yr, 104 patients (28%) relapsed: 53 of 157 (33.8%) in the initial group and 51 of 214 (23.8%) in the recent group. Median time to relapse was 7 mo. Lymphovascular invasion (p<0.0001) and pure embryonal carcinoma (p=0.02) were independent predictors of recurrence; 125 patients (33.7%) were designated as high risk based on the presence of one or both factors. In the initial cohort, 66 of 157 patients (42.0%) were high risk and 36 of 66 patients (54.5%) relapsed versus 17 of 91 low-risk patients (18.7%) (p<0.0001). In the recent cohort, 59 of 214 patients (27.6%) were high risk and 29 of 59 had a recurrence (49.2%) versus 22 of 155 low-risk patients (14.2%) (p<0.0001). Three patients (0.8%) died from testis cancer. The estimated 5-yr disease-specific survival was 99.3% in the initial group and 98.9% in the recent one. ConclusionsNon–risk-adapted surveillance is an effective, simple strategy for the management of all stage I NSGCT.

Primary Retroperitoneal Lymph Node Dissection in Patients With Clinical Stage IS Testis Cancer

Initial management for clinical stage IS (persistently increased tumor markers) nonseminomatous germ cell tumor has evolved from primary retroperitoneal lymph node dissection to induction chemotherapy at most medical centers. We analyzed the outcome in patients treated with primary retroperitoneal lymph node dissection. We reviewed the charts of patients who underwent retroperitoneal lymph node dissection at Brigham and Women's Hospital, and Dana Farber Cancer Center from 1993 to 2008. All patients with clinical stage IS were identified and perioperative data were obtained. A total of 280 patients who underwent retroperitoneal lymph node dissection were identified, of whom 24 identified with clinical stage IS underwent primary dissection. Median followup was 2.9 years. Histopathology revealed an embryonal carcinoma component in 24 orchiectomy specimens (100%) with associated teratoma in 15 (63%). Positive lymph nodes were identified at retroperitoneal lymph node dissection in 9 patients (38%), including pure embryonal carcinoma in 6 (67%), combined embryonal carcinoma and teratoma in 1, embryonal carcinoma, choriocarcinoma and teratoma in 1, and only teratoma in 1. Of the patients who underwent primary retroperitoneal lymph node dissection 5 (21%) also received chemotherapy postoperatively, which was due to persistently increased tumor markers in 3 (13%). No retroperitoneal recurrence was noted on followup imaging. At surgery estimated blood loss was 175 cc, operative time was 3.1 hours and hospital stay was 3.9 days. There were no deaths. Patients with clinical stage IS are at significant risk for metastatic disease and can be successfully treated with primary retroperitoneal lymph node dissection, thereby sparing chemotherapy in most of them. Retroperitoneal recurrence is essentially eliminated when retroperitoneal lymph node dissection is performed in this select patient group.

Functional glutathione S-transferase genotypes among testicular germ cell tumor survivors: associations with primary and post-chemotherapy tumor histology

The pathogenesis of testicular germ cell tumor (TGCT) remains unknown. The aim of this study was to evaluate the pathogenic role of functional polymorphisms in detoxification enzymes among TGCT patients, through association studies of constitutive genotypes and medical parameters before and after chemotherapy. Germline deletion polymorphisms in the glutathione S-transferase mu 1 (GSTM1) and the GST theta 1 (GSTT1), and a functional single nucleotide polymorphism in GST pi 1 (GSTP1, Ile105Val), were analyzed in TGCT survivors (TCSs) (n = 675) and controls (n = 189). Statistical analyses were performed for the genotype distributions between the TCSs and control populations, and between the genotypes and clinicopathological parameters of the TCSs. The GST genotypes showed comparable distributions among the TCSs and the control population. However, the genotype combination GSTT1positive/GSTP1-GG or GSTP1-AG/GSTM1positive was more frequent among the TCSs [P = 0.050, odds ratio (OR): 1.47, 95% confidence interval (CI): 0.998-2.165]. The combined genotype GSTT1positive/GSTP1AA/GSTM1positive was associated with decreased risk of development of pure embryonal carcinoma (P = 0.009, OR: 0.309, 95% CI: 0.122-0.784) and the GSTP1-A-allele (i.e. genotypes GSTP-AA or GSTP-AG) was also associated with decreased risk for development of pure teratoma (P = 0.032, OR: 0.326, 95% CI: 0.122-0.873). Furthermore, the GSTP1-A-allele was overrepresented within the 'good prognosis group' (P = 0.032, OR: 2.407, 95% CI: 1.060-5.469), whereas the GSTM1nulltype was associated with the extent of TC qualifying as 'poor prognosis group' (P = 0.025, OR: 2.839, 95% CI: 1.104-7.301). The GSTP1-AG genotype was associated with necrosis in the tumor's post-chemotherapy histology (P = 0.001, OR: 16.087, 95% CI: 1.930-134.087). Failure, after platinum-based chemotherapy, was associated with the GSTT1positive/GSTP-AA or GSTP-GG/GSTM1-positive genotype (P = 0.019, OR: 2.168, 95% CI: 1.130-4.160). This study confirms an association between the GSTP1-G-allele and TGCT. Combinations of GST genotypes were associated with primary and post-chemotherapy tumor histology, and prognostic group presentation.

High risk NSGCT: case for surveillance

Active surveillance, primary retroperitoneal lymph node dissection and adjuvant chemotherapy are treatment options for high-risk clinical stage (CS) I nonseminomatous germ cell testicular tumors (NSGCT). Since 1981, at Princess Margaret Hospital, Toronto, initial active surveillance with treatment delayed until relapse has been the preferred management option for all CS I NSGCT, regardless of baseline risk of relapse which has allowed us to better define and assess the natural history of high-risk tumors. From 1981 to 2005, 371 patients with CS I NSGCT were placed on an active surveillance protocol. Recurrence patterns, predictors of relapse, disease specific (DS) and overall survival (OS) were measured. Outcomes were stratified into two cohorts by their time of diagnosis [initial, 157 patients (1981-1992); recent, 214 patients (1993-2005)]. Median follow-up was 6.3 years. Median time to relapse was 7.1 months. Lympho-vascular invasion (P < 0.0001) and pure embryonal carcinoma (P = 0.02) were independent predictors of relapse. In the initial cohort, 66/157 (42.0%) were high-risk and 36/66 (54.5%) relapsed versus 17/91 (18.7%) low-risk (P < 0.0001). In the recent cohort, 59/214 (27.6%) patients were high-risk and 29/59 (49.2%) recurred, versus 22/155 (14.2%) low-risk (P < 0.0001). The 5-year DSS and OS were 99.2 and 98.2%, respectively. Nonrisk adapted active surveillance is the preferred management strategy for all CS I NSGCT patients including those at high-risk, providing near 100% cure rate with reduced overall treatment burden. Approximately half of the high-risk patients will be spared unnecessary treatment with little or no increase risk.

Postchemotherapy Laparoscopic Retroperitoneal Lymph Node Dissection in Nonseminomatous Germ-Cell Tumor

Postchemotherapy retroperitoneal lymph node dissection (RPLND) remains essential in the management of metastatic testicular carcinoma and represents a surgical challenge. We determined to assess the feasibility and complications of laparoscopic RPLND in patients who were treated with induction chemotherapy for testis cancer. We performed a retrospective analysis of data that was prospectively recorded from 26 patients who underwent laparoscopic RPLND postplatinum-based chemotherapy between 2000 and 2006. The surgical technique consisted of excision of the residual mass plus unilateral template dissection. A transperitoneal technique was used in 24 patients, and an extraperitoneal approach was used in 2 patients. Operative details, perioperative morbidity data, and histologic findings were assessed for the study. Primary pathologic evaluation of the testis tumor revealed pure embryonal carcinoma in 4 patients, teratocarcinoma in 1 patient, and mixed nonseminomatous germ-cell tumors in 21 patients. All patients had residual disease in the retroperitoneum on a preoperative CT scan, with a median size of 3.4 cm (range 2-6 cm). Procedures in three (11.5%) patients were converted to open surgery. Median operative time was 183 minutes (range 120-260 min). Median estimated blood loss was 400 mL (range 100-600 mL), and blood transfusion was necessary in one patient. Median hospital stay was 5 days (range 2-6 d). Median number of lymph nodes obtained on final histologic examination was 7 (range 4-13). Perioperative complications included eight lymphovascular and one intestinal. At a mean follow-up of 27 months (range 14-36 mos), no recurrences have been observed and no patient was lost to follow-up. Postchemotherapy laparoscopic RPLND is technically feasible. The most frequent complications and causes of conversion are lymphovascular.

Coexistencia de dos tumores germinales seminomatoso y no seminomatoso con una presentación clínica inhabitual

The existence of non seminomatous mixed germ cell tumors of the testis is a frequent event in urologic oncology. Nevertheless, the presence of both components, seminomatous and non seminomatous, in a germ cell tumor is unusual. We present a case of pure classic seminoma of the testis with a lymph node metastasis of pure embryonal carcinoma, with confirmatory immuohistochemical study and clinical outcome of the patient. A 34-year-old man presented with 3 cm supraclavicular tumor. CT scan also revealed multiple metastases in lymph nodes, liver, kidney and left adrenal gland. Tumor markers were negative and the biopsy performed discovered a lymph node metastasis of embryonal carcinoma of probable testicular origin. Ultrasound revealed a 6 mm hypoechoic nodule in the right testis. Orchyectomy was performed and pathologic analysis demonstrated a tumor, 1 cm of diameter, histopathologically compatible with classical seminoma with pagetoid extension to rete testis. Albuginea and spermatic cord did not present neoplastic involvement. Currently the patient is being treated with chemotherapy. The interest of the case is to remark an unusual aggressive clinical presentation as well as to perform a bibliographic review with emphasis in the theories regarding heterogeneous differentiation and spontaneous regression of germ cell tumors of the testis.

Initial versus recent outcomes with a non–risk adapted surveillance policy in stage I non-seminomatous germ cell tumors (NSGCT)

5021 Background: Since 1981 the Princess Margaret Hospital testicular cancer group has used surveillance as the preferred management option for all patients (pts) with clinical stage I NSGCT. In a report of the first 105 pts [Sturgeon et al. J Clin Oncol, 1992] the relapse rate was 35% and the disease specific 5-year survival 99%. Improvements in imaging technique over time could cause stage migration with an overall lower relapse rate in this patient population. We compare our experience with surveillance over different time points. Methods: Three-hundred and five pts with stage I NS-GCT were placed on an active surveillance protocol between 1981–2004. They were not stratified by risk and only received treatment on the event of a relapse. Recurrence rates, time to relapse, risk factors predictive for recurrence, disease specific and overall survival were determined. For the analysis by time period, pts were divided in two groups based on diagnosis date. (Initial=1981–1992 [N=141] and Recent=1993–2004 [N=164]). Results: With a median follow-up of 6.3 years, 77/305 pts (25%) relapsed; 46/141 pts (32.6%) in the initial group and 31/164 (18.9%) in the recent. All but 3 (4%) relapses occurred within 2 years after orchiectomy with a median time to relapse of 7 months. A multivariate analysis established lympho-vascular invasion (p&lt;0.01) and pure embryonal carcinoma (p= 0.03) as independent predictors of recurrence. Overall 104/305 (34.1%) pts were designated as ‘high- risk’ based on the presence of at least one of these factors. In the initial group 60/141 (42.6%) pts were high risk and 32/60 (53%) relapsed versus 14/81 (17.3%) low-risk (p=0.047). In the recent group 44/164 (26.8%) pts were high-risk and 17/44 (38.6%) recurred, versus 14/120 (11.7%) low-risk (p&lt;0.001). There were 2 (0.7%) deaths due to testis cancer. The estimated 5-year disease specific survival was 98.9% in the initial group and 100% in the recent one. Conclusions: Surveillance is an effective strategy for the management of all stage I NSGCT. A risk-adapted policy would result in more than 50% of the patients being unnecessarily treated. The relapse rate has reduced over time, likely due to improvements in imaging causing stage migration. No significant financial relationships to disclose.

Spontaneous regression of testicular germ cell tumors: an analysis of 42 cases: Balzer BL, Ulbright TM, Department of Pathology, Stanford University Hospital and Clinics, Stanford, CA

Spontaneous regression of testicular germ cell tumors (GCTs) is a well-recognized phenomenon but has been incompletely characterized. Many pathologists are not familiar with the findings that support a diagnosis of a “burnt-out” primary in a patient with metastatic GCT. We therefore report the clinical, gross, and histologic findings in 42 cases of testicular GCT that showed either complete (26) or greater than 50% scarring (16) Thirty-seven patients (88%) had either known GCT metastasis or some residual testicular GCT, and none had treatment before orchiectomy. The patients were 17 to 67 years old, with a median of 32. Thirty presented with symptoms of metastasis, 7 with a testicular mass, 2 with elevated human chronic gonadotropin, and 1 with testicular pain. In 2 patients the presentation was unknown. Two patients had prior orchiopexy; another had an intraabdominal testis, and 2 others had prior contralateral seminoma (20 and 42 years previously). Gross descriptions in 37 cases identified white to tan scars, 0.6 to 2.4 cm, in 33. These were circumscribed in 16, with 15 of these having nodular or multinodular configurations and 1 a band-like appearance. In 9 cases the scar was ill defined or stellate, and in 8 cases no further details concerning the scar configuration were available. In 4 cases no scar was apparent; 2 of these had received intraoperative biopsy. Microscopically, all cases showed circumscribed to irregular foci of scarring, distinct from the adjacent parenchyma, in association with widespread testicular atrophy. Other common features were lymphoplasmacytic infiltrates in the scars (37/42) and “ghost” tubules in scars (31/42). Less common features in the scars included angiomatous foci (22/42), siderophages (15/42), and coarse intratubular calcifications (6/42); in the surrounding testis they included intratubular germ cell neoplasia, unclassified (IGCNU) (22/42), Leydig cell prominence (18/42), and necrosis (5/42). Tubular microliths occurred in 13 cases, 12 peripheral to the scar and 1 within it. Metastases in 31 cases were: pure seminoma (17, 3 with residual testicular seminoma), mixed GCT with seminoma (4, 3 with residual testicular seminoma), mixed nonseminomatous GCT (4, 3 with residual testicular GCT), pure embryonal carcinoma (2), pure teratoma (2, 1 with residual testicular teratoma), and pure yolk sac tumor (2). In 5 cases with clinically diagnosed metastases, there was no histologic documentation of the nature of the metastatic tumor. Testicular tumors in the remaining 6 cases having residual primaries without concomitant metastases were pure seminoma (3), mixed GCT with seminoma (2), and pure embryonal carcinoma (1). The most specific histologic findings of a regressed GCT are a distinct scar in association with either IGCNU or coarse intratubular calcifications; however, many cases lack the latter 2 features. In such cases additional features supportive of regressed GCT include testicular atrophy, microlithiasis and, in the scar, lymphoplasmacytic infiltrates and prominent vascularity. Ghost tubules in many scars are not evidence of a non-neoplastic process but likely reflect regression of tumors with intertubular growth. Intertubular growth is a common finding in seminoma, which is the single most frequent type of regressed GCT, occurring either in pure or mixed form in the metastases of 68% (21/31) of the cases and identifiable in 62% (10/16) of persistent testicular tumors. We conclude that regression of testicular GCTs shows a distinctive constellation of findings that usually permits its recognition. In contrast, nonspecific atrophy lacks distinct scars, and scars from non-neoplastic causes lack most of the associated findings seen in our cases.

Immunohistochemical detection of p63 in testicular germ cell neoplasia

p63 is a novel transcription factor-encoding gene with sequence homology to p53. p63 proteins have epithelial stem-cell regulatory functions and play a critical role in tissue development. Study of p63 expression in testicular germ cell tumors has been limited. Thirty-four archival cases of testicular germ cell neoplasia were examined and stained with monoclonal anti-p63 antibody 4A4 using standard methods. Included were 19 seminomas, 1 pure teratoma, 3 pure embryonal carcinomas, 1 pure yolk sac tumor, and 10 mixed germ cell tumors. p63 staining was consistently positive in teratomas in areas of squamous differentiation and in basal reserve-like cells in foci of respiratory/endodermal differentiation. Strong p63 staining was observed within cytotrophoblasts of choriocarcinoma (1/1), whereas focal positivity was detected in embryonal carcinomas (4/10) and yolk sac tumors (2/5). Seminomas and intratubular germ cell neoplasia were p63-negative. These findings may suggest the presence of pluripotent p63-positive stem cell-like nests in yolk sac tumors and embryonal carcinomas or may represent areas of an occult teratoma phenotype undetectable histopathologically on hemotoxylin-eosin sections. p63 positivity in cytotrophoblasts of choriocarcinoma is consistent with gynecologic studies, possibly reflecting the role of p63 in the oncogenesis of neoplastic trophoblasts. The consistent p63 negativity in seminomas may reflect a precommitted embryonic precursor-like phenotype.

Spontaneous Regression of Testicular Germ Cell Tumors

Spontaneous regression of testicular germ cell tumors (GCTs) is a well-recognized phenomenon but has been incompletely characterized. Many pathologists are not familiar with the findings that support a diagnosis of a "burnt-out" primary in a patient with metastatic GCT. We therefore report the clinical, gross, and histologic findings in 42 cases of testicular GCT that showed either complete (26) or greater than 50% scarring (16). Thirty-seven patients (88%) had either known GCT metastasis or some residual testicular GCT, and none had treatment before orchiectomy. The patients were 17 to 67 years old, with a median of 32. Thirty presented with symptoms of metastasis, 7 with a testicular mass, 2 with elevated human chronic gonadotropin, and 1 with testicular pain. In 2 patients the presentation was unknown. Two patients had prior orchiopexy; another had an intraabdominal testis, and 2 others had prior contralateral seminoma (20 and 42 years previously). Gross descriptions in 37 cases identified white to tan scars, 0.6 to 2.4 cm, in 33. These were circumscribed in 16, with 15 of these having nodular or multinodular configurations and 1 a band-like appearance. In 9 cases the scar was ill defined or stellate, and in 8 cases no further details concerning the scar configuration were available. In 4 cases no scar was apparent; 2 of these had received intraoperative biopsy. Microscopically, all cases showed circumscribed to irregular foci of scarring, distinct from the adjacent parenchyma, in association with widespread testicular atrophy. Other common features were lymphoplasmacytic infiltrates in the scars (37/42) and "ghost" tubules in scars (31/42). Less common features in the scars included angiomatous foci (22/42), siderophages (15/42), and coarse intratubular calcifications (6/42); in the surrounding testis they included intratubular germ cell neoplasia, unclassified (IGCNU) (22/42), Leydig cell prominence (18/42), and necrosis (5/42). Tubular microliths occurred in 13 cases, 12 peripheral to the scar and 1 within it. Metastases in 31 cases were: pure seminoma (17, 3 with residual testicular seminoma), mixed GCT with seminoma (4, 3 with residual testicular seminoma), mixed nonseminomatous GCT (4, 3 with residual testicular GCT), pure embryonal carcinoma (2), pure teratoma (2, 1 with residual testicular teratoma), and pure yolk sac tumor (2). In 5 cases with clinically diagnosed metastases, there was no histologic documentation of the nature of the metastatic tumor. Testicular tumors in the remaining 6 cases having residual primaries without concomitant metastases were pure seminoma (3), mixed GCT with seminoma (2), and pure embryonal carcinoma (1). The most specific histologic findings of a regressed GCT are a distinct scar in association with either IGCNU or coarse intratubular calcifications; however, many cases lack the latter 2 features. In such cases additional features supportive of regressed GCT include testicular atrophy, microlithiasis and, in the scar, lymphoplasmacytic infiltrates and prominent vascularity. Ghost tubules in many scars are not evidence of a non-neoplastic process but likely reflect regression of tumors with intertubular growth. Intertubular growth is a common finding in seminoma, which is the single most frequent type of regressed GCT, occurring either in pure or mixed form in the metastases of 68% (21/31) of the cases and identifiable in 62% (10/16) of persistent testicular tumors. We conclude that regression of testicular GCTs shows a distinctive constellation of findings that usually permits its recognition. In contrast, nonspecific atrophy lacks distinct scars, and scars from non-neoplastic causes lack most of the associated findings seen in our cases.

Reasons for gender differences in prescription of drug therapies in rheumatoid arthritis-results from the database of the German collaborative arthritis centres

We identified 109 testicular tumors, including pure and mixed germ cell tumors and sex cord–stromal tumors, and conducted immunohistochemical staining for CDX2, DOG1, and GATA3 to address the potential utility of these readily available and commonly used markers in the evaluation of testicular tumors. Their expression has not been previously thoroughly examined in testicular germ cell tumors. The distribution, percentage, and intensity of positivity were assessed. CDX2 was positive in all yolk sac tumors, 25% of choriocarcinomas, 9% of seminomas, and 4% of embryonal carcinomas (sensitivity for yolk sac tumor, 100%; specificity, 89% [teratomas excluded]). CDX2 also stained glandular components within teratomas and identified inconspicuous yolk sac tumor components in 3 cases previously diagnosed as pure embryonal carcinoma. GATA3 was positive in all choriocarcinomas (sensitivity, 100%). Weak GATA3 immunostaining was also seen in 12% of yolk sac tumors and 2 of 2 primitive neuroectodermal tumors. DOG1 was negative in all tumors, but stained spermatocytes and spermatids and the luminal borders of the epididymis and rete testis of nonneoplastic testis. We conclude that CDX2 is a sensitive and relatively specific marker for yolk sac tumor among the nonteratomatous germ cell tumors. It may serve to screen for yolk sac tumor components often overlooked on hematoxylin and eosin–stained slides. GATA3 is helpful in the recognition of trophoblastic cells, especially of intermediate type. DOG1 is a sensitive marker for spermatocytes and needs to be further studied for its significance.