Adult Extragonadal Germ Cell Tumors

Genitourinary Imaging Pictorial Essay Shinagare et al. Extragonadal Germ ell Tumors Genitourinary Imaging Pictorial Essay Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved tul. Shinagare 1,2 Jyothi P. Jagannathan Nikhil H. Ramaiya Matthew N. Hall nnick D. Van den bbeele Shinagare, Jagannathan JP, Ramaiya NH, Hall MN, Van den bbeele D Keywords: adult, extragonadal germ cell tumor, primary, metastases DOI:10.2214/JR.09.4103 Received December 10, 2009; accepted after revision March 14, 2010. 1 ll authors: Department of Imaging, Dana-Farber ancer Institute, 44 inney St., oston, M 02115. ddress correspondence to.. Shinagare (ashinagare@partners.org). 2 ll authors: Department of Radiology, righam and Women s Hospital, oston, M. WE This is a Web exclusive article. JR 2010; 195:W274 W280 0361 803X/10/1954 W274 merican Roentgen Ray Society dult Extragonadal Germ ell Tumors OJETIVE. The purpose of this article is to describe the key imaging features of primary and metastatic extragonadal germ cell tumors in adults. ONLUSION. Extragonadal germ cell tumors primarily affect men during the third and fourth decades of life. Their imaging characteristics are nonspecific, and extragonadal germ cell tumors should always be included in the differential diagnosis of a midline anterior mediastinal or retroperitoneal mass. Levels of human chorionic gonadotropin or α-fetoprotein or both may be elevated, depending on the histologic subtype. E xtragonadal germ cell tumors account for 1 5% of all germ cell tumors [1]. The most widely accepted theory suggests that extragonadal germ cell tumors arise from primordial germ cells misplaced during their migration to gonads [2]. Klinefelter syndrome (47 XXY) is the only known predisposing factor [3]. The clinical course is variable, with a potential for aggressive behavior and widespread metastases. Extragonadal germ cell tumors are considered metastases from occult or burned out gonadal cancer until proved otherwise [4]. If a primary testicular tumor is detected, the extragonadal mass is always considered metastatic. Testicular palpation is insufficient to exclude a primary testicular tumor, and ultrasound should be performed in all cases [5]. burned out gonadal primary tumor is a regressed tumor that presents with a metastasis, which is seen as an echogenic scar or a hypoechoic tissue on ultrasound [6]. Routine gonadal biopsy to rule out intratubular germ cell neoplasia is not recommended [7]. Ultrasound can also be used to follow up patients with extragonadal germ cell tumors for delayed development of gonadal tumors. Extragonadal germ cell tumors are usually seen in children or young adults and typically arise in midline locations. In adults, the most common sites of primary extragonadal germ cell tumors are, in descending order, the mediastinum, retroperitoneum, and cranium. In children, the cranium and sacrococcygeal region are the common sites. The literature on the metastatic pattern of the primary extragonadal germ cell tumors is sparse. In this article, we discuss the different types of extragonadal germ cell tumors in adults, their typical locations, radiologic and FDG PET/T features, and patterns of metastatic spread. lassification of Extragonadal Germ ell Tumors Histologically, extragonadal germ cell tumors comprise seminomas (30 40%) and nonseminomatous tumors (60 70%) in men and dysgerminomas and nondysgerminomas in women. Nonseminomatous germ cell tumors (NSGTs) include teratoma, embryonal carcinoma, endodermal sinus tumor (yolk sac tumor), choriocarcinoma, and tumors with mixed histology. Tumors with even a small proportion of nonseminomatous elements are classified as nonseminomatous tumors. NSGTs usually have a more aggressive course than do seminomatous tumors [8 10]. The majority of the extragonadal germ cell tumors occur in men, except benign mature teratoma, which occurs with equal frequency in men and women [9]. Tumor markers, though nonspecific, are helpful in the diagnosis and follow-up of extragonadal germ cell tumors. Levels of human chorionic gonadotropin (i.e., β-hg) are elevated in choriocarcinoma, embryonal carcinoma, and in about 10% of cases of seminomas. W274 JR:195, October 2010

Extragonadal Germ ell Tumors Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved Levels of serum α-fetoprotein are elevated in endodermal sinus tumors and embryonal carcinoma. Primary Mediastinal Germ ell Tumor The mediastinum is the most common site of extragonadal germ cell tumors [11], constituting 50 70% of all extragonadal germ cell tumors. In adults, extragonadal germ cell tumors account for 15% of primary anterior mediastinal tumors [12]. More than half of mediastinal germ cell tumors are mature teratomas. mong malignant mediastinal germ cell tumors, 40% are seminomas and 60% are nonseminomatous tumors. Seminoma The peak incidence of seminoma is seen in the third and fourth decade of life. Seminomas produce a bulky lobulated homogeneous mildly enhancing mass on T (Fig. 1). ysts, hemorrhage, and calcification are rarely seen. On MRI, seminomas have a nonspecific intermediate signal on both T1- and T2-weighted images and show a relatively homogeneous enhancement. Seminomas (Fig. 2) are more FDG avid than are nonseminomas [13]. Local invasion is uncommon, but most patients have metastases at presentation, most often to the lymph nodes and less commonly to the lungs, bone, or liver [10]. Nonseminomatous Germ ell Tumors Yolk sac tumor (Fig. 3) is the most common mediastinal NSGT (60%), followed by mixed tumors (18%), choriocarcinoma (12%) (Fig. 4), and embryonal carcinoma (9%) [8] (Fig. 5). Most of them present in the fourth decade of life. haracteristics of mixed tumors (Fig. 6) depend on the relative proportion of various components. On T, NSGTs are usually large, lobulated, and heterogeneous, with calcification, hemorrhage, and necrosis [14, 15]. On MRI, the cystic or necrotic areas appear hyperintense on T2-weighted images. T1 hyperintensities are seen in more than 50% of cases, corresponding to areas of hemorrhage. Fat planes between these tumors and adjacent organs are often obliterated [14]. Invasion of adjacent organs, including chest wall, lung, mediastinal vessels, and pericardium (Fig. 3), may be present. bout 35% of patients have metastases at presentation, with liver (Fig. 3) and lung (Fig. 4) as the most common sites, followed by lymph nodes (Fig. 5), brain (Fig. 4), and bones [16]. Local recurrence in the mediastinum or chest wall may occur (Fig. 7). The main role of FDG PET lies in detection of viable tumor in the residual mass after chemotherapy (Fig. 6), for which it has the highest specificity [13]. FDG PET is also useful in the evaluation of recurrent disease [17] (Fig. 7), particularly in the context of increased tumor markers and negative crosssectional imaging. Teratoma Teratomas are the most common mediastinal germ cell tumor, accounting for 70% of cases, and they usually arise in or near the thymus. Teratomas may be mature (benign; Fig. 8) or immature (with variable malignant potential; Fig. 9). Malignant teratomas usually have mixed histology, with the presence of elements of other germ cell tumors. Mature teratomas appear as well-defined lobulated heterogeneous solid or cystic anterior mediastinal masses. One fourth to one third of mature teratomas have calcification present. On MRI, the fat component causes T1 hyperintensity, the cystic component results in high signal on T2-weighted images and low signal on T1-weighted images, and calcifications cause magnetic susceptibility artifacts. Mature teratoma may be non FDG avid [18] (Fig. 8). Differential Diagnosis Diagnosis of extragonadal germ cell tumors should always be considered when a bulky lobulated anterior mediastinal mass is present in a young male. Seminoma is a likely possibility if the mass is homogeneous and only mildly enhancing. combination of calcification, fat, fluid, and soft tissue in an anterior mediastinal mass is diagnostic of teratoma [19]. However, the radiologic findings of other nonseminomatous tumors are often nonspecific, and tissue diagnosis is almost always needed for differentiation from other common mediastinal masses, such as lymphomas, thymic neoplasms, metastatic lymph nodes, thyroid masses, and neurogenic tumors. Primary Retroperitoneal Germ ell Tumor Most retroperitoneal germ cell tumors are metastases from primary testicular germ cell tumors. Primary retroperitoneal germ cell tumors account for about 10% of all primary malignant retroperitoneal tumors and about 30 40% of extragonadal germ cell tumors. The imaging features of the retroperitoneal seminomas and nonseminomas are similar to those of their mediastinal counterparts. Retroperitoneal extragonadal germ cell tumors are usually large at presentation. Encasement, displacement, and compression of the abdominal vessels are common (Fig. 10). There are no definite radiologic features distinguishing primary retroperitoneal germ cell tumors from lymphoma, retroperitoneal metastases, and retroperitoneal soft-tissue sarcoma. rain (Fig. 10), liver (Fig. 10), lungs (Fig. 10), and bones (Fig. 11) are the common sites of metastases. Patients may present with metastases. Skeletal metastases are usually lytic and may be associated with a soft-tissue mass. Rarely, extragonadal germ cell tumors, most commonly the teratomatous element, undergo sarcomatous or carcinomatous transformation [20] (Fig. 12). lthough retroperitoneal seminomas have a prognosis similar to that of mediastinal seminomas, retroperitoneal NSGTs have a better prognosis than do their mediastinal counterparts [10]. Primary Intracranial Germ ell Tumor Intracranial germ cell tumors are seen mainly in adolescents and young adults. Pineal and suprasellar regions are the most frequent intracranial sites [21] (Fig. 13). Intracranial germ cell tumors usually present as discrete enhancing masses, often containing calcification, and usually are associated with hydrocephalus. In conclusion, the anterior mediastinum and retroperitoneum are the most common sites of primary extragonadal germ cell tumors. Extragonadal germ cell tumors have a variable clinical course, with the potential for aggressive behavior and widespread metastases. The imaging characteristics of these tumors are nonspecific, and the definitive diagnosis of extragonadal germ cell tumor requires a biopsy. Usually, seminomas appear as lobulated homogeneous masses with mild contrast enhancement and marked FDG uptake, whereas nonseminomatous tumors usually appear as inhomogeneous infiltrating masses with variable degrees of FDG uptake. The presence of calcification and fatdensity areas should prompt a possibility of teratoma. These radiologic findings, in combination with other clinical data, including tumor markers, should always lead to consideration of extragonadal germ cell tumors in the differential diagnosis of a bulky midline thoracoabdominal mass in an adult male. JR:195, October 2010 W275

Shinagare et al. Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved References 1. McKenney JK, Heerema-McKenney, Rouse RV. Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations. dv nat Pathol 2007; 14:69 92 2. haganti RS, Rodriguez E, Mathew S. Origin of adult male mediastinal germ-cell tumours. Lancet 1994; 343:1130 1132 3. Hasle H, Mellemgaard, Nielsen J, Hansen J. ancer incidence in men with Klinefelter syndrome. r J ancer 1995; 71:416 420 4. oulier, Lefebvre Y, de Visscher L, et al. Metastases of clinically occult testicular seminoma mimicking primary extragonadal retroperitoneal germ cell tumors. JR-TR 2008; 91:139 144 5. ohle, Studer UK, Sonntag RW, Scheidegger JR. Primary or secondary extragonadal germ cell tumors? J Urol 1986; 135:939 943 6. ngulo J, González J, Rodríguez N, et al. linicopathological study of regressed testicular tumors (apparent extragonadal germ cell neoplasms). J Urol 2009; 182:2303 2310 7. Krege S, eyer J, Souchon R, et al. European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ ell ancer onsensus group (EGG). Part I. Eur Urol 2008; 53:478 496 8. Moran, Suster S, Koss MN. Primary germ cell tumors of the mediastinum. Part III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum a clinicopathologic and immunohistochemical study of 64 cases. ancer 1997; 80:699 707 9. Weidner N. Germ-cell tumors of the mediastinum. Semin Diagn Pathol 1999; 16:42 50 10. okemeyer, Nichols R, Droz J, et al. Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J lin Oncol 2002; 20:1864 1873 11. Dehner LP. Germ cell tumors of the mediastinum. Semin Diagn Pathol 1990; 7:266 284 12. Ueno T, Tanaka YO, Nagata M, et al. Spectrum of germ cell tumors: from head to toe. RadioGraphics 2004; 24:387 404 13. remerius U, Effert PJ, dam G, et al. FDG PET for detection and therapy control of metastatic germ cell tumor. J Nucl Med 1998; 39:815 822 14. Levitt RG, Husband JE, Glazer HS. T of primary germ-cell tumors of the mediastinum. JR 1984; 142:73 78 15. lomlie V, Lien HH, Fosså SD, Jacobsen, Stenwig E. T in primary malignant germ cell Fig. 1 48-year-old man with primary mediastinal seminoma., ontrast-enhanced axial T image through chest shows large well-defined homogeneous soft-tissue density mass with minimal contrast enhancement in posterior mediastinum, partially surrounding thoracic aorta., Unenhanced chest T scan performed after three cycles of treatment with etoposide, cisplatin, and bleomycin shows dramatic response. Minimal residual soft tissue (arrow) is noted posterolateral to esophagus. tumors of the retroperitoneum. cta Radiol 1991; 32:155 158 16. Fizazi K, uline S, Droz JP, et al. Primary mediastinal nonseminomatous germ cell tumors: results of modern therapy including cisplatin-based chemotherapy. J lin Oncol 1998; 16:725 732 17. achmann J, Ernestus K, Werner T, et al. Detection of primary choriocarcinoma in the mediastinum by F-18 FDG positron emission tomography. lin Nucl Med 2007; 32:663 665 18. Spermon J, De Geus-Oei LF, Kiemeney LLM, Witjes J, Oyen WJG. The role of (18)fluoro-2- deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours. JU Int 2002; 89:549 556 19. Suzuki M, Takashima T, Itoh H, et al. omputed tomography of mediastinal teratomas. J omput ssist Tomogr 1983; 7:74 76 20. thanasiou, Vanel D, El Mesbahi O, Theodore, Fizazi K. Non-germ cell tumours arising in germ cell tumours (teratoma with malignant transformation) in men: T and MR findings. Eur J Radiol 2009; 69:230 235 21. Jennings MT, Gelman R, Hochberg F. Intracranial germ-cell tumors: natural history and pathogenesis. J Neurosurg 1985; 63:155 167 Fig. 2 47-year-old man with primary mediastinal seminoma. Fused FDG PET/T image through chest in axial plane shows FDG-avid anterior mediastinal mass (maximum standardized uptake value, 11.7). W276 JR:195, October 2010

Extragonadal Germ ell Tumors Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved Fig. 3 38-year-old man with primary mediastinal yolk sac tumor., ontrast-enhanced chest T scan shows bulky anterior mediastinal mass with large central unenhancing necrotic region and peripheral heterogeneously enhancing solid component., ontrast-enhanced abdominal T scan obtained 2 months later shows rapid progression with multiple large liver metastases., ontrast-enhanced chest T scan obtained at same time as image shown in panel shows presence of pericardial invasion (arrows), which was confirmed on echocardiography (not shown). Patient died within 1 month. Fig. 4 33-year-old woman with primary mediastinal choriocarcinoma., ontrast-enhanced chest T scan shows lobulated heterogeneous mediastinal mass with presence of left hilar lymphadenopathy (arrow). Patient also had supraclavicular lymphadenopathy at time of presentation (not shown)., ontrast-enhanced chest T scan. Lung windows show multiple pulmonary metastases present at time of presentation., Patient developed multiple brain metastases while receiving chemotherapy with etoposide, ifosfamide, and cisplatin. Unenhanced axial brain T scan shows multiple hyperdense hemorrhagic metastases (arrowheads) with edema (arrow) and mild midline shift to left side. Fig. 5 26-year-old man with mediastinal embryonal carcinoma., ontrast-enhanced chest T scan shows bulky lobulated midline mediastinal mass showing subtle areas of heterogeneity. Mass encases mediastinal vessels and trachea. ilateral pleural effusions are seen (arrows)., ontrast-enhanced neck T scan shows multiple enlarged cervical lymph nodes (arrow) with presence of calcification (arrowhead). Mass effect is noted on neck vessels and on right lobe of thyroid., MR venography in coronal plane shows large neck mass (arrowheads) with tumor invasion of superior vena cava (arrows). JR:195, October 2010 W277

Shinagare et al. Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved Fig. 6 22-year-old man with primary anterior mediastinal mixed germ cell tumor comprising 90% seminoma, 5% embryonal carcinoma, and 5% teratoma., Unenhanced chest T scan shows large midline anterior mediastinal mass with amorphous calcification, pleural nodules (arrow), and small left pleural effusion (arrowhead)., Multiple calcified pleural-based masses (arrowheads) are better appreciated on unenhanced chest T scan image. Pleural effusion is seen (arrow)., Fused axial FDG PET/T image of chest after three cycles of treatment with bleomycin, etoposide, and cisplatin shows significant regression of anterior mediastinal mass with mild persistent FDG uptake (arrowheads). Maximum standardized uptake value of residual mass was 3.2. lood pool activity was 1.8. Fig. 7 32-year-old man with resected mixed nonseminomatous germ cell tumor of mediastinum, comprising predominant yolk sac tumor and embryonal carcinoma (primary tumor not shown)., Fused axial FDG PET/T image shows multifocal FDG-avid chest wall recurrence (arrowheads). Maximum standardized uptake value of more anterior chest wall mass was 11.8, and that of mass in lateral chest wall was 10.4., ontrast-enhanced abdominal T scan performed 3 months later shows peritoneal spread (arrows) and multiple nodules in left lower chest wall. Some chest wall nodules show central low-density necrotic component (arrowhead). Fig. 8 51-year-old-woman with anterior mediastinal mature teratoma. Fused axial FDG PET/T through chest shows well defined non-fdg-avid mediastinal mass (straight arrow) with areas of calcification (curved arrow) and fat attenuation (arrowhead). Maximum standardized uptake value of mass was 1.8. lood pool activity was 2.3. Fig. 9 30-year-old man with anterior mediastinal immature teratoma., oronal contrast-enhanced T image shows large anterior mediastinal mass with areas of fat attenuation (arrows)., T1-weighted MR image again shows large anterior mediastinal mass with areas of T1-hyperintense signal (arrow) caused by fat component. W278 JR:195, October 2010

Extragonadal Germ ell Tumors Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved Fig. 10 62-year-old man who presented with headache, vomiting, and left arm clumsiness., rain MR FLSH image shows solitary lesion in right parietal region (arrow), with susceptibility artifacts due to hemorrhage and surrounding edema (arrowheads). Patient was later proved to have primary retroperitoneal tumor containing embryonal carcinoma and yolk sac tumor., Further investigation with contrast-enhanced abdominal T showed necrotic retroperitoneal mass (white dot) partially encasing aorta (curved arrow) and displacing inferior vena cava (straight arrow). Multiple liver metastases (arrowheads) are seen. Histopathology revealed 70% embryonal carcinoma and 30% yolk sac tumor., oronal contrast-enhanced chest T image shows metastases in lung (arrowheads) and liver (arrow). D Fig. 11 53-year-old man with primary retroperitoneal mixed germ cell tumor containing 90% teratoma, 5% seminoma, and 5% endodermal sinus tumor., ontrast-enhanced axial abdominal T image shows heterogeneous retroperitoneal mass (arrow) with areas of low density., ontrast-enhanced axial chest T image shows expansile lytic rib metastasis (arrow)., Sagittal T1-weighted MR image shows focal T1- hypointense areas in L4 (arrow) and S1 (arrowhead) vertebrae without involvement of adjacent intervertebral disks, representing metastases. D, Follow-up contrast-enhanced abdominopelvic T scan shows progression of lytic metastasis involving sacrum (arrowhead) and left iliac bone with associated soft tissue (arrows). JR:195, October 2010 W279

Shinagare et al. Downloaded from www.ajronline.org by 46.3.196.204 on 01/19/18 from IP address 46.3.196.204. opyright RRS. For personal use only; all rights reserved Fig. 12 24-year-old man who presented with palpable right supraclavicular lymph node., Lymph node (arrow) is seen on contrast-enhanced axial chest T image. On biopsy, node showed mixed germ cell tumor comprised of teratoma and embryonal carcinoma., Further evaluation with contrast-enhanced abdominal T revealed retroperitoneal mass (arrow). iopsy of mass revealed embryonal rhabdomyosarcoma arising in association with teratoma. Fig. 13 26-year-old man with primary intracranial mixed seminoma and embryonal carcinoma in pineal region. ontrast-enhanced axial T scan of head shows enhancing mass (straight arrow) containing calcification (curved arrow) and causing hydrocephalus (arrowheads). W280 JR:195, October 2010