An Evaluation of the Eighth Edition of the American Joint Committee on Cancer (AJCC) Staging System for Retroperitoneal Sarcomas Using the National Cancer Data Base (NCDB): Does Size Matter?

OBJECTIVES: Retroperitoneal sarcomas (RPS) are often large at diagnosis calling into question the seventh edition AJCC size classification of <5 cm (T1) or ≥5 cm (T2). The eighth edition expands T stage into 4 categories (T1: ≤5 cm, T2: 515 cm). We evaluated the prognostic ability of the eighth edition using the National Cancer Database (NCDB). METHODS: Patients with RPS treated between 1998 and 2011 were identified from the NCDB; overall survival (OS) was compared. RESULTS: Of the 6427 patients identified, 9% had tumors ≤5 cm (n=580), 19.4% 515 cm (n=3045). With the eighth edition, stage II patients (G2/3 ≤5 cm) have a similar OS to stage IIIA patients (G2/3 5 cm10 cm) show a decrease in OS. Tumor size as a continuous variable had a modest effect on survival (HR, 1.004; P=0.04). On multivariate analysis, higher T-stage was associated with decreased OS (T4 HR, 1.3; P<0.001) but high grade and incomplete resection (R2) were stronger prognostic factors. The c-index for both editions were similar (80.13 eighth vs. 80.08 seventh). CONCLUSIONS: The eighth edition AJCC staging system for retroperitoneal sarcoma incorporates larger tumor size parameters that better characterize most patients, but tumor size alone is only a modest predictor of outcome.

Nefrectomía parcial laparoscópica: estudio comparativo entre la vía transperitoneal y la vía retroperitoneal / Laparoscopic partial nephrectomy: Comparative study of the transperitoneal pathway and the retroperitoneal pathway

Introducción: La nefrectomía parcial laparoscópica es el tratamiento recomendado en aquellos tumores con un tamaño inferior a 4 cm en los cuales sea factible. Dependiendo de la localización del tumor se considerará la vía transperitoneal (VTP) o la vía retroperitoneal directa(VRP). Objetivo: Comparar las nefrectomías parciales VTP y VRP realizadas entre 2007-2016. Material y métodos: Estudio retrospectivo de 71 pacientes sometidos a VTP (42) y VRP (29). Se han evaluado características propias de los pacientes y del tumor, incluyendo la complejidad tumoral (PADUA, RENAL,C-index). Se compararon variables perioperatorias, incluyendo las complicaciones, entre ambas vías. Resultados: No encontramos diferencias en cuanto a edad, género, Charlson o IMC. Encontramos una mayor proporción de pacientes con cirugía mayor abdominal previa en la VRP (7,1 vs. 24,1%; p = 0,043). No hallamos diferencias en el tamaño, en la lateralidad ni la polaridad, ni en la complejidad de los tumores en ninguno de los scores evaluados. Encontramos diferencias significativas en la localización del tumor (anterior/medio/posterior) entre la VTP y la VRP (54,8/31/14,3 vs. 3,4/13,8/82,8%; p < 0,001). No encontramos diferencias en el tiempo quirúrgico ni en los días de estancia. La VTP presentó una menor apertura de la vía urinaria (4,8 vs. 27,6%; p = 0,007) y un mayor porcentaje de pacientes con renorrafia hemostática (47,6 vs. 17,2%; p = 0,008). No se encontró diferencia en la necesidad de isquemia caliente, en los cambios en la hemoglobina ni en el filtrado glomerular. La tasa de complicaciones es similar entre ambas series. Conclusión Ambas vías muestran resultados similares en cuanto a la preservación de la función renal, las complicaciones y los resultados oncológicos. A pesar de ello, consideramos que es recomendable conocer ambas técnicas y adaptar el tipo de acceso al caso clínico

Introduction: Laparoscopic partial nephrectomy is the recommended treatment for tumours smaller than 4 cm in cases where it is feasible. Depending on the location of the tumour, the transabdominal or direct retroperitoneal pathway may be considered. Objective: To compare the transperitoneal (TPPN) and direct retroperitoneal (RPPN) partial nephrectomies performed between 2007 and 2016. Material and methods: A retrospective study was conducted on 71 patients who underwent TPPN (42) or direct RPPN (29) partial nephrectomy. We evaluated the characteristics of the patients and tumours, including tumour complexity (PADUA, RENAL, C-index). We compared perioperational variables, including the complications between the 2 pathways. Results: We found no differences in terms of age, sex, Charlson's score and BMI. A larger proportion of patients in the direct RPPN group had prior major abdominal surgery (7.1 vs. 24.1%; P = .043). There were no differences in tumour size, laterality, polarity or complexity in any of the assessed scores. There were significant differences in tumour location (anterior/middle/posterior) between the TPPN and RPPN groups (54.8/31/14.3 vs. 3.4/13.8/82.8%; P < .001). There were no differences in the surgical time or length of stay. The TPPN group had a smaller urinary tract opening (4.8 vs. 27.6%; P = .007) and a higher percentage of haemostatic renorrhaphy (47.6 vs. 17.2%; P = .008). There were no differences in the need for warm ischaemia, in the changes in haemoglobin levels or in the glomerular filtration rate. The complication rates were similar for the two series. Conclusion: The two pathways show similar results in terms of renal function preservation, complications and oncological results. However, we recommend understanding both techniques and adapting the access type to the clinical case

Pathology of retroperitoneal sarcomas: A brief review.

Sarcomas represent a highly heterogeneous group of tumors as reflected in the significant overlap between their histologic phenotypes between the different types, posing diagnostic challenges for the pathologist. Definitive tumor classification is increasingly important because of prognostication and emergence of targeted therapies for some of the sarcoma types. In this review, we highlight pertinent pathologic and molecular aspects of sarcomas common in the retroperitoneum, relevant to the surgical oncologist.

Performance Analysis of the American Joint Committee on Cancer 8th Edition Staging System for Retroperitoneal Sarcoma and Development of a New Staging Algorithm for Sarcoma-Specific Survival.

BACKGROUND: The American Joint Committee on Cancer (AJCC) recently published the 8th edition of the AJCC Cancer Staging Manual. Major changes were made to the staging algorithm for retroperitoneal sarcoma; however, whether these changes improve staging system performance is questionable. METHODS: This retrospective cohort analysis of 3703 adult patients with retroperitoneal sarcoma in the Surveillance, Epidemiology, and End Results (SEER) database compares a novel staging system incorporating histologic subtype of sarcoma with current and prior AJCC soft tissue sarcoma staging systems using multiple statistical techniques. The effect of tumor size on sarcoma-specific survival was also assessed by flexible, non-linear Cox proportional hazard regression using restricted cubic splines and fractional polynomials. RESULTS: The relationship between the covariate-adjusted log hazard for disease-specific survival and tumor size is non-linear. Although the new AJCC T classification approximates this hazard fairly well, the overall prognostic impact of tumor size is limited after accounting for other predictive factors. Predictive accuracy and concordance indices of the AJCC 8th edition staging system for retroperitoneal sarcoma are significantly lower than the prior 7th edition. A proposed staging system incorporating histologic grade, tumor size, and histologic subtype is superior to both the AJCC 7th and 8th editions in predicting sarcoma-specific survival. CONCLUSION: AJCC committees should not revise tumor staging algorithms unless the changes actually improve the staging system. A proposed staging scheme incorporating data regarding histologic subtype of sarcoma performs significantly better than both the 7th and 8th AJCC staging systems.

[Surgical treatment of retroperitoneal masses]. / Khirurgicheskoe lechenie neorgannykh zabriushinnykh opukholei.

AIM: To improve the results of treatment of patients with retroperitoneal tumors. MATERIAL AND METHODS: The study included 83 patients with retroperitoneal tumors including 57 cases of benign tumors and 26 patients with malignancies. Laparotomy (Lt), robot-assisted (RA) and laparoscopic (Ls) techniques were used in 35, 34 and 14 patients respectively. Median tumor sizes in the largest dimension were 102 mm, 75 mm and 81.5 mm in Lt, RA and Ls groups respectively. RESULTS: Average time of surgery was 112.5 minutes in Lt-group, 140 min in RA group and 125 minutes in Ls group. Median blood loss was 125 ml, 50 ml and 50 ml in the same groups respectively. Conversion was performed in 1 patient during RA-surgery and in 7 patients during laparoscopy. Postoperative complications occurred in 6 patients after laparotomy and in 5 patients after RA-intervention. There were no deaths. CONCLUSION: Comprehensive evaluation of different surgical methods is necessary to achieve successful treatment of retroperitoneal tumors. Conventional approach is indicated for tumors over 10 cm while minimally invasive techniques are justified for tumors less than 10 cm. RA-interventions facilitates surgery for tumors located in difficult areas and small anatomical spaces as well as for neoplasms adjacent to great vessels.

SEOM Clinical Guideline of management of soft-tissue sarcoma (2016)

Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5 cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes (AU)

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Prognostic reclassification of patients with intermediate-risk metastatic germ cell tumors: Implications for clinical practice, trial design, and molecular interrogation.

OBJECTIVES: Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. PATIENTS AND METHODS: Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. RESULTS: A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22-31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥ 10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81-223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1-79.0) and 86.2% (81.7-91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12-1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6-84.3), and it was 86.7% (95% CI: 82.0-91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. CONCLUSIONS: A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.

Schawannoma retroperitoneal interaorto-cava. A propósito de un caso / Retroperitoneal schwannoma betwen the aorta and vena cava. A case report

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Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value.

AIMS: Well-differentiated leiomyosarcomas show morphologically recognizable smooth muscle differentiation, whereas poorly differentiated tumours may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. The expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between the morphological spectrum and the muscle marker expression profile of leiomyosarcoma, and the impact of these factors on patient outcomes. METHODS AND RESULTS: Tissue microarrays including 202 non-uterine and 181 uterine leiomyosarcomas with a spectrum of tumour morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumours frequently lost one or more conventional smooth muscle markers [smooth muscle actin, desmin, h-caldesmon, and smooth muscle myosin (P < 0.0001)], as well as the more recently described markers SLMAP, MYLK, and ACTG2 (P < 0.0001). In primary tumours, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (P = 0.0111 and P = 0.043, respectively). Patients with muscle marker-enriched tumours (expressing all four conventional markers or any three of ACTG2, CFL2, CASQ2, MYLK, and SLMAP) had improved overall survival (P < 0.05) in univariate analyses. CONCLUSIONS: Morphologically and immunohistochemically, poorly differentiated leiomyosarcomas can masquerade as undifferentiated pleomorphic sarcomas with progressive loss of muscle markers. The expression of muscle markers has prognostic significance in primary leiomyosarcomas independently of tumour morphology.

Accuracy of preoperative percutaneous biopsy for the diagnosis of retroperitoneal liposarcoma subtypes.

BACKGROUND: Surgery is the primary treatment for all subtypes of retroperitoneal liposarcoma, but neoadjuvant therapy may be warranted in cases of dedifferentiated liposarcoma (DDLS), which has an increased risk of recurrence and metastasis. Therefore, an accurate subtype-specific diagnosis is vital for appropriate consideration of neoadjuvant therapy. Previous studies assessing the subtype-specific accuracy of percutaneous biopsy are limited. We aimed to analyze the accuracy of preoperative percutaneous biopsy in the subtype-specific diagnosis of retroperitoneal liposarcoma and thus the reliability of percutaneous biopsy in guiding decisions about neoadjuvant treatment. METHODS: We retrospectively reviewed the medical records, including the pathologic reports, interventional radiology reports, and operative reports, of patients registered in the retroperitoneal/well-differentiated liposarcoma (WDLS/DDLS) database at The University of Texas MD Anderson Cancer Center between 1993 and 2013. RESULTS: We identified 120 patients who underwent 137 preoperative percutaneous biopsies followed by surgical resections. Pathologic examination following resection indicated that 74 of the patients had WDLS and 63 had DDLS. The overall diagnostic accuracy of percutaneous biopsy for identifying the subtype of liposarcoma was 62.8 % (86/137); the accuracy for identifying WDLS was significantly higher (85.1 %; 63/74) than that for identifying DDLS (36.5 %; 23/63) (p < 0.01). CONCLUSIONS: Percutaneous biopsy has low accuracy in the diagnosis of retroperitoneal DDLS. This can potentially mislead physicians in the decision to implement neoadjuvant treatment. When developing treatment strategies, including clinical trials for patients with retroperitoneal liposarcoma, physicians should carefully consider the low accuracy of percutaneous biopsy in detecting DDLS.

Computed tomography manifestations of histologic subtypes of retroperitoneal liposarcoma.

OBJECTIVE: Liposarcoma (LPS) is the most common soft tissue sarcoma and accounts for approximately 20% of all mesenchymal malignancies, often occurring in deep soft tissue of retroperitoneal space. Accurate preoperative diagnosis is therefore necessary. We explored whether computed tomography (CT) could be used to differentiate between the various types of retroperitoneal liposarcoma (RPLS). METHOD: Forty-seven cases of RPLS, diagnosed surgically and histologically, were analyzed retrospectively. CT features were correlated with postoperative pathological appearance. RESULTS: The study radiologist identified 29, 11, 2, 2 and 3 RPLS as atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL), dedifferentiated liposarcoma (DDL), myxoid/round cell liposarcoma (ML/RCL), pleomorphic liposarcoma (PL) and mixed-type liposarcoma. Analysis of CT scans revealed the following typical findings of the different subtypes of RPLS: ALT/WDL was mainly visible as a well-delineated fatty hypodense tumor with uniform density and integrity margin; DDL was marked by the combination of focal nodular density and hypervascularity. ML/RCL, PL and mixed liposarcoma showed malignant biological behaviour and CT findings need further studies. CONCLUSIONS: CT scanning can reveal important details including internal components, margins and surrounding tissues. Based on CT findings, tumor type can be roughly evaluated and biopsy location and therapeutic scheme guided.

Seminoma: reporte de un caso / Seminoma: case report

De las patologías testiculares, las neoplasias son las más comunes en estos órganos. Se presenta el caso de paciente de 32 años de edad, con diagnóstico de seminoma con único antecedente de trauma testicular hace 12 años. Los hallazgos quirúrgicos fueron cordones espermáticos engrosados y masa testicular derecha de 10 x 10 cm. Acompañándose de un proceso linfoproliferativo que involucra región retroperitoneal y que engloba la aorta abdominal y desplaza la vena cava inferior hacia la derecha. La lesión mide 125.9 x 56.8 x 118.1 mm ubicada en región supra e infrapúbica. El diagnóstico anatomopatológico del tumor testicular es de un Seminoma clásico. Discusion: El seminoma es una neoplasia testicular rara (Estados Unidos reporta aproximadamente 0.4 casos por millón de habitantes) de crecimiento lento, que se puede acompañar o no de dolor es común en el adulto mayor, y muy raro en pacientes jóvenes. En este caso, la neoplasia se presentó a los 23 años y fue de crecimiento lento y dolorosa en el testículo derecho...(AU)

Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy?

BACKGROUND: Unlike novel molecular-targeted therapies for metastatic gastrointestinal stromal tumors (GIST), conventional treatments for peritoneal sarcomatosis (PS) are mostly ineffective. As with carcinomatosis of epithelial origin, a rationale base supports an aggressive locoregional treatment of PS, but the use of CRS and HIPEC in this setting is still controversial. We assessed the outcome of clinically and pathologically homogeneous subsets of patients with PS uniformly treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A prospective database of 37 patients who underwent CRS and close-abdomen HIPEC with cisplatin and doxorubicin or mitomycin-C was reviewed. PS originated from GIST (pre-imatinib era) in 8 patients, uterine leiomyosarcoma (ULS) in 11, retroperitoneal liposarcoma (RPLP) in 13, and other sarcoma in 5. RESULTS: CRS was macroscopically complete in 28 patients (75.7%). Operative mortality was 3.7% and morbidity 21.6%. After median follow-up of 104 (range, 1-131) months, peritoneal disease progression occurred in 16 patients, distant metastases in 5, and both in 13. For all patients, median overall survival was 26.2 months; 7 patients were alive at 46-130 months (ULS, n = 4; RPLP, n = 2; GIST, n = 1). RPLP had the best overall survival (median, 34 months) but 100% peritoneal relapse; GIST had dismal overall, local-regional-free and distant-free survival; ULS had the higher proportion of long survivors and best local-regional-free survival. CONCLUSIONS: Overall, results of CRS and HIPEC did not compare favorably to those of conventional therapy. In a subgroup analysis, the combined approach did not change GIST and RPLS natural history. The interesting results with ULS may warrant further investigations.

[Result of treatment for advanced germ cell tumor in the last decade].

PURPOSE: We retrospectively analyzed our therapeutic results of advanced male germ cell tumors in terms of efficacy and feasibility of our treatment strategy. PATIENTS AND METHODS: Fifty-one new cases were treated in Saitama Cancer Center between April 1997 and August 2007. Patients age ranged from 16 to 58 (median 33). Primary site of the tumor was testis in 41 (80%) patients, retroperitoneum in 6 (12%), and mediastinum in 4 (8%). Histology of the primary germ cell tumor was pure seminoma in 14 (27%), and non-seminoma in 30 (59%). Twenty (39%), 14 (27%) and 17 (33%) were classified as good-, intermediate-, and poor-risk, retrospectively, based on The International Germ Cell Consensus Classification (IGCCC) criteria. The initial treatment for good-risk patients was BEP x 3. Intermediate- or poor-risk patients were treated by VIP from 1997 to 2000, VIPVB from 2001 to 2004, and BEP from 2005 to 2007. Second line salvage treatments were high-dose VIP or ICE from 1997 to 2000. TIP x 4 has been employed since. Marker-negative cases with residual tumors underwent surgical resection of the mass lesion. RESULTS: Five-year survival rate was 100%, 74%, and 76% in patients with good-, intermediate- and poor-risk characteristics, respectively. After two courses of initial chemotherapy, tumor marker decline was satisfactory in 37 patients (73%) and unsatisfactory in 14 (27%). Of these 14 patients, 12 (86%) had unsatisfactory hCG decline, 4 (29%) had unsatisfactory AFP decline, and 2 (14%) had unsatisfactory decline in both markers. Five-year overall survival was 94% in cases with satisfactory maker decline and 71% in those with unsatisfactory marker decline (p = 0.03). CONCLUSIONS: In this IGCCCG era, 5 year survival rates of the advanced germ cell tumors have improved by the earlier administration of second line chemotherapies based on both the prognostic factor-based staging system and the tumor marker decline in initial chemotherapy. Development of effective treatment for cases with unfavorable tumor maker decline is the most challenging issue to be addressed.

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis.

Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.

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.