Clinical utility of the AJCC 8th edition pT1 subclassification and impact on practice patterns in stage I seminoma.

BACKGROUND: The American Joint Committee on Cancer 8th edition staging guidelines for testicular cancer established a 3 cm cutoff to subclassify stage T1 seminomas (<3 cm = pT1a and ≥3 cm = pT1b). The efficacy of this cutoff in predicting metastatic disease and impact on treatment patterns have not been studied. METHODS: We retrospectively reviewed patients with pT1 testicular seminoma in the National Cancer Database from 2004 to 2016. Receiver operating curves were used to determine the efficacy of the 3 cm tumor cutoff in identifying metastatic disease, and multivariable regression was used to compute the effect of tumor size on the rate of adjuvant therapy among Stage I patients. RESULTS: A total of 10,134 patients with pT1 seminoma were evaluated. The current size cutoff of 3 cm for subclassification did not exhibit high discrimination in identifying metastatic disease (area under receiver operating curve: 0.546). Surveillance has grown as the preferred treatment after orchiectomy -32.1% in 2004 to 81.2% in 2015. However, the rate of adjuvant therapy for pT1, Stage I seminomas associated positively with tumor size even with adjustment for year of diagnosis. For tumors above 3 cm, the odds ratio stabilized around 1.9. By using the 3 cm cutoff to guide adjuvant therapy, up to 85% of T1b patients may be overtreated. CONCLUSION: The 3 cm cutoff for subclassification of Stage I seminoma does not predict metastatic recurrence but is associated with increased receipt of adjuvant therapy. A 3 cm cutoff and the pT1a/b classification may therefore contribute to overtreatment in many young patients with a long life expectancy for whom minimizing adverse effects should be prioritized.

Clinical implications of the American Joint Committee on Cancer (AJCC) 8th edition update in seminoma pT1 subclassification.

BACKGROUND: Seminoma accounts for 30-50% of testicular germ cell tumors (TGCT)-the most common solid malignancy in men aged 15-35 years. The American Joint Committee on Cancer (AJCC) 8th edition (2018) created the subclassifications pT1a (tumor size < 3 cm) and pT1b (≥ 3 cm), despite not being universally recognized. Rete testis invasion (RTI) and tumor size > 4 cm are considered features associated with a higher recurrence risk, but not formally used for staging. The authors propose further understanding the subclassification's potential impact in clinical practice, by summarizing current evidence and reviewing clinical cases in their institutions. METHODS: All consecutive cases of seminoma stage I, pT1 treated in two institutions between January 2005 and December 2016 were included. Clinical data were retrieved, and variables were analyzed using SPSS. Relevant literature on the topic was reviewed. RESULTS: Seminoma pT1 was identified in 58 patients. By using newly AJCC criteria, 29 (50%) would have been staged as pT1a and 29 (50%) pT1b. Median age at diagnosis was similar (33 in pT1a vs 32 in pT1b). Median follow-up time 5.8 years. Almost half (45%) of pT1b patients had a tumor size < 4 cm. The majority of either pT1a or pT1b were treated with chemotherapy or radiotherapy, reflecting more intensive approaches in the past. Three retroperitoneal recurrences were recorded (two in pT1a, one in pT1b, all under surveillance protocol); no deaths occurred. RTI and extensive necrosis (EN) were associated with pT1b (P <  0.0001 and P = 0.023, respectively), known adverse biological features. CONCLUSIONS: In our population, the exploratory analysis of the newly created AJCC criteria showed no significant difference in recurrence or death, although pT1b was associated with adverse biomarkers, such as RTI and EN, but its clinical relevance remains incompletely understood. Our results confirm an excellent prognosis, regardless of subcategorization, thus a larger population and a longer follow-up time are needed to understand prospectively the impact of the recently updated criteria. We would recommend using the latest AJCC staging system, although the individual risk of relapse, long-term toxicities and patient preferences should be taken into account when considering surveillance or active treatment adjuvant options.

MicroRNA and transcription factor co-regulatory networks and subtype classification of seminoma and non-seminoma in testicular germ cell tumors.

Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≥90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes.

Contemporary North-American population-based validation of the International Germ Cell Consensus Classification for metastatic germ cell tumors of the testis.

BACKGROUND: The International Germ Cell Consensus Classification (IGCCC) is the recommended stratification scheme for newly diagnosed metastatic seminoma (mSGCT) and non-seminoma germ cell tumor (mNSGCT) patients. However, a contemporary North-American population-based validation has never been completed and represented our focus. MATERIALS AND METHODS: We identified mSGCT and mNSGCT patients within the SEER database (2004-2015). The IGCCC criteria were used for stratification into prognostic groups. Kaplan-Meier (KM) derived actuarial 5-year overall survival (OS) rates were calculated. In addition, cumulative incidence plots tested cancer-specific (CSM) and other-cause mortality (OCM) rates. RESULTS: Of 321 mSGCT patients, 190 (59.2%) and 131 (40.8%), respectively, fulfilled good and intermediate prognosis criteria. Of 803 mNSGCT patients, 209 (26.1%), 100 (12.4%), and 494 (61.5%), respectively, fulfilled good, intermediate, and poor prognosis criteria. In mSGCT patients, actuarial KM derived 5-year OS was 87% and 78% for, respectively, good and intermediate prognosis groups (p = 0.02). In cumulative incidence analyses, statistically significant differences were recorded for CSM but not for OCM between good versus intermediate prognosis groups. In mNSGCT patients, actuarial KM derived 5-year OS was 89%, 75% and 60% for, respectively, good, intermediate, and poor prognosis groups (p < 0.001). In cumulative incidence analyses, statistically significant differences were recorded for both CSM and OCM between good, intermediate, and poor prognosis groups. CONCLUSIONS: Our findings represent the first population-based validation of the IGCCC in contemporary North-American mSGCT and mNSGCT patients. The recorded OM rates closely replicate those of the original publication, except for better survival of poor prognosis mNSGCT patients.

Reclassification of good-risk seminoma: prognostic factors, novel biomarkers and implications for clinical management.

Germ cell tumors represent 11% of the cancers diagnosed in adolescent males and are the most common solid tumors in adult men between the ages of 20 and 35. Pure seminoma accounts for around 50% of all testicular germ cell tumors. The prognostic classification of the International Germ Cell Cancer Collaborative Group for good-prognosis seminoma includes both nodal disease and pulmonary visceral metastases. In this article, we analyzed recent data on prognosis and outcome of good-prognosis seminoma to revise the traditional classification of the disease and improve tailored treatment.

[Testicular germ cell tumors: Histopathological and molecular features]. / Tumeurs germinales du testicule : caractéristiques histopathologiques et moléculaires.

In 2016, the WHO classification of testicular germ cell tumors was revised considering advances in the understanding of their tumorigenesis and molecular features. This restructuring led to a division into two major groups with, on one hand, prepubertal-type tumors, not derived from germ cell neoplasia in situ (GCNIS), and on the other hand, postpubertal-type tumors, GCNIS-derived, which occur in youg men (seminoma and non seminomatous germ cell tumors - embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma essentially). The term germ cell neoplasia in situ is consensually accepted as a new terminology for the precursor lesion. In this new classification, the term "spermatocytic seminoma" is replaced by "spermatocytic tumor", reclassified among non-GCNIS-derived tumors. The purpose of this change of nomenclature is to reflect the usually non-aggressive behaviour of this tumor and to avoid any confusion with usual seminoma. The spectrum of trophoblastic tumors continues to expand with the description of new rare entities such as the cystic trophoblastic tumor, the placental site trophoblastic tumor and the epithelioid trophoblastic tumor. This review aims to provide a focus on testicular germ cell tumors highlighting the new immunohistochemical and molecular features responsible for the restructuring of classification. The TNM staging is presented according to the AJCC 8th edition 2017 update.

Incorporating age into International Germ Cell Consensus Classification (IGCCC): a time to move forward?

BACKGROUND: Older age is a poor prognostic indicator among patients with germ cell tumors. The current study evaluates an age-integrated international germ cell consensus classification (IGCCC) for advanced germ cell tumors. METHODS: SEER database (2004-2014) was accessed through SEER*Stat program and both IGCCC and age-integrated IGCCC were calculated based on site of the primary, site of the metastasis and level of tumor markers. Overall survival analyses according to IGCCC and age-integrated IGCCC were conducted through Kaplan-Meier analysis. RESULTS: Overall survival was compared according to IGCCC and age-integrated IGCCC for patients with seminoma and Non-seminomatous germ cell tumors (NSGCTs). P values were significant (P <0.001) for all scenarios. c-index for seminoma for IGCCC was 0.553; c-index for seminoma for age-integrated IGCCC was 0.664;c-index for NSGCTs for IGCCC was 0.729; and c-index for NSGCTs for age-integrated IGCCC was 0.738. A Cox-regression multivariate model of factors affecting cancer-specific survival (adjusted for race and surgical treatment) was conducted. All P values for pair wise comparisons (among different age-integrated IGCCC categories) were significant for both seminoma and NSGCTs (P<0.01). CONCLUSION: Compared to traditional IGCCC, age-integrated IGCCC is more discriminatory and the new risk groups introduced within it are prognostically relevant.

Long-term cardiovascular complications in stage I seminoma patients

Purpose. The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients. Methods. This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate. Results. During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025). Conclusion. We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation (AU)

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Canine testicular tumors: two types of seminomas can be differentiated by immunohistochemistry.

BACKGROUND: Testicular tumors are the most common genital neoplasms in male dogs, with Leydig cell tumors (LCT), seminomas (SEM), and Sertoli cell tumors (SCT) the most common forms. Human SEM are classified as classical (CSEM) or spermatocytic (SSEM). Intratubular germ cell neoplasia of undifferentiated origin (IGCNU) is another form of human testicular tumor. The aim of this study was to verify that CSEM/SSEM classification is valid in dogs and confirm the existence of canine IGCNU. RESULTS: Testicular tumors were found in 46% of dogs at necropsy and accounted for 7% of tumors biopsied. The median age of dogs with tumors at necropsy was 10.16 years; median age at positive biopsy was 10.24 years. The most common tumors, in decreasing order, were LCT, mixed tumors, SEM and SCT at necropsy, and SEM, SCT, mixed tumors, LCT, peripheral nerve sheath tumor, and teratoma in the biopsy group. IGCNU was found in 3% of testicles at necropsy and in 3% of biopsy samples. Two dogs had testicular tumor metastasis. Expression of c-KIT was most common in SEM and seminomatous components of mixed tumors. PLAP was mostly expressed in IGCNU, SEM, teratoma, and some mixed tumors. Cytokeratin was mainly expressed in SCT. CD30 expression was low in both groups. CONCLUSIONS: The high tumor incidence at necropsy can be attributed to older age. Tumor incidence in biopsy samples, dog age, and histological classification were consistent with previous studies. The higher incidence of SEM and SCT in the biopsy group probably resulted from the obvious clinical expression of these tumor types. The low incidence of metastasis confirmed the predominance of benign tumors. Low CD30 expression confirmed the low incidence of testicular embryonal carcinoma. Cytokeratin helps differentiate stromal tumors, especially SCT, from germ cell tumors. Histology and c-KIT and PLAP expression indicate that IGCNU exists in dogs. Expression of c-KIT and PLAP confirmed that CSEM and SSEM classification is valid in dogs.

Spermatocytic seminoma: a 21 years' retrospective study in a tertiary care hospital in Pakistan.

BACKGROUND: Spermatocytic seminoma is a rare testicular germ cell tumor of old men. Accounting for 1-4% of all seminomas, spermatocytic seminomas have distinct pathogenesis, histological features, immunohistochemical profile and comparatively benign clinical behavior which distinguishes them from other germ cell tumors, especially classic seminoma. AIMS: The purposes of our study were to assess the patient demographics, pathological features and to evaluate the utility of CD 117 immunostain along with other immunohistochemical stains in distinguishing Spermatocytic seminomas from classic seminomas. MATERIAL AND METHODS: All spermatocytic seminomas patients diagnosed during 1992 to 2013 at Section of Histopathology, Department of Pathology and Microbiology, Aga Khan University hospital were included. Patient characteristics, histological details and follow-up data of few patients were available. CD 117 expression was determined by immunohistochemistry. RESULTS: Total 16 cases of Spermatocytic seminomas were reviewed. Median age was 60 years and average tumor size was 10.4 cms. Microscopically, all of the 16 cases showed presence of edema and absence of lymphocytic infiltrate and intratubular germ cell neoplasia. Cytoplasmic glycogen was negative in all 13 cases, PLAP immunostain was negative in all 12 cases, while CD 117 was positive in all 8 cases, where applied. CONCLUSION: CD 117 is of limited utility in differentiating the spermatocytic seminoma from classic seminoma as it is expressed in significant number of spermatocytic seminomas. However, different histological features, PAS special stain and PLAP immunostain are significantly helpful in distinguishing these two entities.

Canine classical seminoma: a specific malignant type with human classifications is highly correlated with tumor angiogenesis.

BACKGROUND: Human seminoma is classified as classical seminoma (SE) and spermatocytic seminoma (SS). Human SE is known to be more malignant and metastasizing more frequently than SS. Tumor angiogenesis is highly related with tumor progression and metastasis, with microvessel density (MVD) being an important parameter of metastatic potential. Canine seminoma is not yet well-established as SE or SS type including correlation with angiogenesis. We classified canine SE and SS, and then compared them to tumor associated vessels. METHODS: Twenty-three cases of canine seminomas (2 intratubular, 9 diffuse, and 12 intratubular/diffuse seminomas showing both intratubular and diffuse patterns) were classified as SE or SS by immunohistochemistry (IHC) using monoclonal antibody against PLAP and by PAS stain. The histopathological data were then compared to see if there was a correlation with SE or SS. Angiogenesis of seminomas were evaluated by immunohistochemical assay using polyclonal antibody against Von Willebrand factor (vWF) and by calculating the means of MVD, vessels area and perimeters using computerized image analysis. Statistical Package for Social Sciences (SPSS) program was used for various statistical analyses. RESULTS: The numbers of PLAP+/PAS+ canine SEs were 8/23 (34.8%) and PLAP-/PAS- SSs were 15/23 (61.2%). All SE cases (8/8, 100%) were intratubular/diffuse types. SS types included 2 intratubular (2/15, 13.3%), 9 diffuse (9/15, 60%), and 4 intratubular/diffuse (4/15, 26.7%) types. MVD and vascular parameters in SEs were significantly higher than in SSs, showing the highest value in the intratubular/diffuse type. Seminomas observed with neoplastic cells invasion of vessels presented higher perimeter and area values than seminomas without conformed neoplastic cells invasion. CONCLUSION: In this study, we demonstrated a positive relationship between canine SE and tumor angiogenesis. Furthermore, we also showed that a tumor cells invasion of vessels were a correlated vascular parameter. Although metastasis of canine seminomas has rarely been reported, our results support that canine SE could have high metastatic potential similar to the human counterpart. Further studies are required to clarify the relationship between canine SE and clinical data with metastatic factors.

[Mediastinal germ cell tumors: anatomopathology, classification, teratomas and malignant tumors]. / Les tumeurs germinales du médiastin: anatomopathologie, classification, tératomes et tumeurs malignes.

Mediastinal germ cell tumors are rare tumors. It is classic to divide those tumors into two categories, seminomas and nonseminomatous germ cell tumors: teratomas (mature or immature), embryonal carcinomas, yolk sac tumors, and choriocarcinomas. Each histological sub-type can be associated to another sub-type that realise a so-called mixed germ cell tumor. Diagnosis strategy is currently well codified for malignant mediastinal germ cell tumors. It greatly benefits from tumoral markers (alpha-fetoprotein and beta human chorionic gonadotrophin). For instance, the treatment strategy still raises some specific problems to each histological type. The treatment of seminomatous tumors is standardised--chemotherapy/surgery on residual tumor greater than 3 cm/radiotherapy on viable persistent residual tumors--and provides very satisfying results. As for the nonseminomatous germ cell tumors, the situation is dramatically different. The treatment strategy is less standardised--association of chemotherapy and surgery--and the prognosis is very severe.

Surveillance following orchiectomy for stage I testicular seminoma: long-term outcome.

OBJECTIVES: To report the long-term outcome of surveillance for stage I seminoma at a single institution in Japan. METHODS: A retrospective review of medical records of 64 patients who underwent orchiectomy between January 1982 and December 2005 was carried out. All of them were managed by surveillance for stage I seminoma. RESULTS: Median follow-up time was 123.8 months. Of the 64 patients, seven developed relapse. Four relapses occurred within the first year after orchiectomy, but three occurred over 4 years after orchiectomy. The actuarial relapse-free rates at 5, 10, and 15 years were 92.1%, 90.0%, and 86.0%, respectively. All patients received salvage chemotherapy at relapse. Four of these seven patients were alive without evidence of disease. One patient died of seminoma and one was alive with this disease. The remaining one patient died of leukemia without secondary relapse of seminoma. T classification was a statistically significant (P = 0.028) risk factor for relapse on univariate analysis. In T1 patients, relapse-free rates at 5, 10, and 15 years were all 97.1%, whereas in T2/T3 patients the corresponding relapse-free rates were 86.4%, 82.1%, and 71.8%, respectively. CONCLUSIONS: The relapse-free rate in the present study was similar to previous reports. Late relapse should be considered during surveillance.

The utility of microscopic findings and immunohistochemistry in the classification of necrotic testicular tumors: a study of 11 cases.

Necrotic testicular tumors are relatively frequent and can present a significant diagnostic challenge. Because of differing treatments for seminomas versus nonseminomas, accurate diagnosis is critical. Eleven totally (n=9) or almost totally (n=2) necrotic testicular tumors were retrieved from our consult files. The submitting pathologists favored benign processes in 4 cases, Leydig cell tumor in 1, and lymphoma in 1. The cases were evaluated for histologic features and, when material was available, by immunostaining with 7 antibodies: keratin (AE1/AE3), OCT4, placental alkaline phosphatase, alpha-fetoprotein (AFP), CD117, CD30, and S100. Only distinct reactivity in a cellular distribution in the necrotic zone was considered positive; nuclear reactivity alone was scored for OCT4 and membrane reactivity for CD117 and CD30. Mean patient age was 35 years (range 16-63). Mean tumor size was 19 mm (range 7-53). All patients presented with unilateral testicular masses (6 right, 5 left); 2 also had acute pain. The combination of histologic features, immunostains and, in 1 case, serum AFP permitted classification of 8 tumors (4 seminomas, 3 embryonal carcinomas, 1 yolk sac tumor). Three were not classifiable. The necrotic seminomas lacked associated coarse intratubular calcifications and were positive for OCT4 (4/4) and CD117 (3/3) but negative for keratin (0/4) and CD30 (0/4). The necrotic embryonal carcinomas had associated coarse intratubular calcifications and were positive for keratin (2/3), OCT4 (2/2), and CD30 (3/3). OCT4 stained 1 unclassifiable tumor, which lacked other specific markers. We did not find placental alkaline phosphatase, AFP, and S100 stains useful, although S100 did highlight tumor "ghost" cells in 1 case. Other features in most cases included intratubular germ cell neoplasia (6/11), tubular atrophy/hyalinization (10/11), tumor "ghost" cells (10/11), scar (9/11), and inflammation (10/11). Of the 5 patients with available follow-up, 3 were free of disease at 1, 5, and 8 years after orchiectomy (2 necrotic seminomas and 1 germ cell tumor, unclassified). One patient with yolk sac tumor (age 63 y) developed widespread metastases after 15 months and died of disease. The final case was initially misinterpreted as "testicular infarction, no malignancy" and 16 months later the patient developed a large retroperitoneal seminoma. Most totally necrotic testicular tumors can be placed into clinically important groups by assessment for coarse intratubular calcifications and staining reactions for keratin, OCT4, CD117, and CD30.

Pattern of germ cell testicular carcinoma in Dharmais Cancer Hospital between January 2000-December 2004.

AIM: to find out the distribution of germ cell tumor based on age, histopathology, stadium, chemotherapy regimen, and number of cases per year in patients hospitalized in Dharmais National Cancer Hospital during the period of January 2000 to December 2004. METHODS: the data were collected from medical record of patients with testicular carcinoma that were treated on inpatient and outpatient basis in Dharmais National Cancer Hospital during the period of January 2000 to December 2004. The data were collected, recorded and analyzed in descriptive manner and presented in tables of distribution and frequency. RESULTS: there were 44 cases testicular carcinoma being analyzed; 40 cases (90.92%) were germ cell tumor, 42.50% aged 21-30 years old; and the most frequent histological type was seminoma (47.50%). About 39.50% of the patients were admitted in stage II of the disease, and 61.59% were put on BEP regimen. Seminoma type was more frequent in >or= 30-year-old age group while on the other hand, non-seminoma was mostly found in

Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors.

The core embryonic stem cell transcription factors (TFs) OCT3/4 (OCT4), NANOG, and SOX2 have shared as well as nonoverlapping roles in stem cell growth and differentiation. These same TFs are also expressed in various types of human germ cell tumors (GCTs), implicating them in regulation of tumor growth and differentiation. Although NANOG and OCT3/4 are sensitive and specific markers for seminoma and embryonal carcinoma, neither factor aids in the clinically important distinction of seminomatous from nonseminomatous tumors. In contrast, expression profiling data suggest that SOX2 may help with this distinction. To determine if a panel of embryonic stem cell TFs (NANOG, OCT3/4, and SOX2) can facilitate the identification and distinction of seminomatous from nonseminomatous GCTs, we evaluated their expression by immunohistochemistry in primary testicular (n=41) and metastatic retroperitoneal (n=43) GCTs. Our results confirm NANOG and OCT3/4 as sensitive and specific markers for primary seminoma and embryonal carcinoma and demonstrate the novel finding that NANOG is a marker for metastatic GCTs. In addition, SOX2 is expressed in embryonal carcinoma but not pure seminoma and is therefore a useful diagnostic marker for distinguishing seminomatous and nonseminomatous GCTs. In summary, we find that the embryonic stem cell TF signature of seminoma is NANOG+, OCT3/4+, and SOX2-, whereas embryonal carcinoma is NANOG+, OCT3/4+, and SOX2+, and expect these immunohistochemical profiles will facilitate the diagnosis of both primary and metastatic GCTs.

Identification of two molecular groups of seminomas by using expression and tissue microarrays.

Highly effective tailored clinical management of testicular germ cell tumors is based on the identification of two major histologic subtypes: seminomatous and nonseminomatous germ cell tumors. Expression array analysis of these two histologic subtypes using hierarchical clustering reveals two tumor groups, one composed solely of seminomas and the other containing embryonal carcinomas and seminomas. Supervised analysis between these groups identified 55 significantly dysregulated genes (false discovery rate = 2.3). The genes with the highest overexpression in the first group compared with the second included SLC43A1 (POV1), NET-7, IGF2, and JUP; down-regulated genes included GRB7, PFKP, and CDC6. In situ hybridization of SLC43A1 mRNA showed significantly increased signal intensity in the seminomas. At the protein level, expression of the immunohistochemical markers cytokeratins (pan-cytokeratin staining), placental-like alkaline phosphatase, anti-cytokeratin clone 5.2, CD30, anion exchanger 1/3, junction plakoglobulin (JUP), and POU domain, class 5, transcription factor 1 (octomer-binding transcription factor 3/4) was significantly different between seminomas and embryonal tumors. Hierarchical clustering based on a refined protein expression profile identified two groups, the first consisting solely of seminomas the other of seminomas and embryonal carcinomas. No histomorphologic differences were observed between the two seminoma groups such as the presence or absence of lymphocytes or extent of stromal elements. In summary, using independent methodologies and samples, we have identified two groups of seminomas. One group of seminomas has a molecular profile similar to embryonal carcinoma. The findings in the current study may help explain aberrant immunoprofiles seen with some seminomas.

Testicular germ-cell tumours in a broader perspective.

The germ-cell tumours are a fascinating group of neoplasms because of their unusual biology and the spectacular therapeutic results that have been obtained in these tumours. Traditionally, this group of neoplasms is presented in an organ-oriented approach. However, recent clinical and experimental data convincingly demonstrate that these neoplasms are one disease with separate entities that can manifest themselves in different anatomical sites. We propose five entities, in which the developmental potential is determined by the maturation stage and imprinting status of the originating germ cell. Recent progress begins to explain the apparent unpredictable development of germ-cell tumours and offers a basis for understanding their exquisite sensitivity to therapy.

Correlation of nuclear morphometric features with animal and human World Health Organization International Histological Classifications of canine spontaneous seminomas.

The aim of this study was to correlate nuclear morphometric features with animal and human World Health Organization International Histological Classifications in canine seminomas. Twenty-three canine seminomas were classified, according to Animal World Health Organization International Histological Classification as intratubular, intratubular with signs of invasion, or diffuse and according to Human World Health Organization International Histological Classification criteria as spermatocytic and typical. The morphonuclear characteristics of tumors were quantitatively evaluated by means of digital cell image analyses of hematoxylin and eosin-stained nuclei. In particular, the mean nuclear area, mean nuclear perimeter, mean nuclear form factor, and their respective standard deviations were calculated. The relationship between the different variables and the tumor histologic types was assessed. On the basis of animal and human classification systems, statistically significant differences were observed only between intratubular seminomas with signs of invasion and the other two types and between spermatocytic and typical seminomas, respectively. In humans, it is well known that typical seminomas are more common and aggressive than spermatocytic ones. In our study, the canine seminomas classified as typical showed significantly larger and more variable nuclear area and perimeter than spermatocytic seminomas. These results support the opinion that most canine seminomas correspond to human spermatocytic seminomas and could explain the benign behavior of canine seminomas, which derive from a more differentiated type of germ cell.