An Overview of Testicular Germ Cell Tumors Armita Bahrami, MD; Jae Y. Ro, MD, PhD; Alberto G. Ayala, MD ● Context.—More than 90% of testicular neoplasms orig- not occur before 5 years of age. Spermatocytic seminoma, inate from germ cells. Testicular germ cell tumors (GCTs) a tumor of elderly men, typically has an indolent clinical are a heterogeneous group of neoplasms with diverse his- behavior, but rarely it undergoes sarcomatous transfor- topathology and clinical behavior. mation associated with an aggressive behavior. Embryonal Objective.—To help the readers distinguish various sub- carcinoma is the most common component in mixed GCTs. types of GCTs, to highlight the clinical manifestations and Eighty percent or more of embryonal carcinoma compo- pathologic features of these tumors, and to review several nent and vascular invasion are recognized predictors of newly developed immunohistochemical markers for GCTs. occult metastasis for clinical stage I mixed GCTs. Most pa- Data Sources.—Review of the pertinent literature and tients with prepubertal yolk sac tumor, the most common our experience. pediatric GCT, have stage I disease at presentation. Most Conclusions.—The etiology of GCTs is largely unknown. choriocarcinomas present with metastatic symptoms be- Cytogenetic studies suggest a different pathogenesis for cause of the propensity for rapid hematogenous dissemi- each group of infantile/prepubertal GCTs, postpubertal nation. Teratomas in children regardless of maturity and GCTs, and spermatocytic seminoma. Unclassified intratu- dermoid cysts in adults are benign; in contrast, teratomas bular germ cell neoplasia is the precursor of all GCTs, ex- in adults have a malignant behavior. With appropriate ther- cluding spermatocytic seminoma and infantile/prepubertal apy, the majority of testicular GCTs are curable. GCTs. Seminoma, the most common GCT in adults, does (Arch Pathol Lab Med. 2007;131:1267–1280) esticular tumors are the most common malignancies vealed an increase in the incidence of GCTs during the T among American men between the ages of 20 and 39 past several decades,10,11 but the reason for such a trend is years.1,2 The American Cancer Society has estimated that unclear. in the year 2006, 8250 men will develop testicular cancers Testicular GCTs are a heterogeneous group of neo- and 370 men will die of these tumors in the United States.3 plasms with diverse histopathology and variable clinical Testis tumors comprise approximately 1% of all cancers in course and prognosis. This diversity is best reflected in men,3,4 but only about 0.1% of cancer deaths in males3 be- various systems offered to classify these tumors.12–17 Cur- cause the majority of these tumors are curable.5 rently the most comprehensive and widely accepted sys- More than 90% of testicular neoplasms originate from tem of classification is the one proposed by the World 6 germ cells. The incidence of testicular germ cell tumors Health Organization,18 which is summarized in Table 1. (GCTs) increases shortly after the onset of puberty and There is some evidence that the origin and biology of peaks in the fourth decade of life with a median age of prepubertal and postpubertal testicular GCTs are distinct 7 34 years at diagnosis. The incidence varies among differ- from each other. First, the distribution pattern of GCTs in ent races and various geographic locations. It is 5 times adults and children is different. Testicular neoplasms in more frequent in white men compared with African 8 adult patients often consist of seminoma, embryonal car- American men. Among nations with the highest reported cinoma, or mixed testicular GCTs. In the pediatric popu- incidence are Scandinavia, Germany, and New Zealand.9 lation, yolk sac tumor and teratoma are the most frequent Despite several recognized risk factors in the develop- tumors; on the contrary, seminoma and embryonal carci- ment of GCTs (eg, cryptorchidism or a prior history of noma are rare.19 Non-GCTs, which account for less than GCT), the pathogenesis of germ cell neoplasms including 10% of testicular neoplasms in adults, comprise as high as the contributing role of environmental factors or genetic susceptibility remains unknown. Reports from the epide- one third of testis tumors in children. Furthermore, al- miologic studies in the United States and Europe have re- though there is a strong association between postpubertal testicular tumors and intratubular germ cell neoplasia, such association has not been observed in prepubertal Accepted for publication November 20, 2006. GCTs. From the Departments of Pathology, Baylor College of Medicine (Dr Genetic studies have shown that postpubertal testis tu- Bahrami), and Weill Medical College of Cornell University, The Meth- mors are often aneuploid with a consistent chromosomal odist Hospital (Drs Ro and Ayala), Houston, Tex. abnormality composed of a gain of short arm of chro- The authors have no relevant financial interest in the products or mosome 12, usually in the form of an isochromosome, companies described in this article. 20 Reprints: Alberto G. Ayala, MD, Department of Pathology, The Meth- i(12p). In contrast tumors arising in prepubertal gonads odist Hospital, Weill Medical College of Cornell University, 6565 Fan- are typically unassociated with 12p amplification and tend nin St, Houston, TX 77030 (e-mail: [email protected]). to be diploid. For these reasons, testicular GCTs have been Arch Pathol Lab Med—Vol 131, August 2007 An Overview of Testicular Germ Cell Tumors—Bahrami et al 1267 Table 1. 2004 World Health Organization Histologic cell neoplasia (eg, intratubular embryonal carcinoma or Classification of Germ Cell Testis Tumors intratubular yolk sac tumor). Intratubular germ cell neo- plasia, unclassified, is known to be the precursor of most Intratubular germ cell neoplasia, unclassified adult GCTs; on the other hand, other types of intratubular ● Tumors of 1 histologic type (pure forms) germ cell neoplasia are developed as an outcome of pag- ● Seminoma ● etoid intratubular spread of their invasive counterpart in Seminoma with syncytiotrophoblastic cells the testicular parenchyma adjacent to a preexisting GCT. ● Spermatocytic seminoma ● Spermatocytic seminoma with sarcoma ● Embryonal carcinoma Pathologic Features ● Yolk sac tumor ● Testes with IGCNU are usually normal in size but can Trophoblastic tumors be smaller than normal. Histologically, IGCNU is charac- ● Choriocarcinoma ● Trophoblastic neoplasms other than choriocarcinoma terized by large primitive atypical cells that are usually ● Monophasic choriocarcinoma twice the size of normal germ cells. These cells lie along ● Placental site trophoblastic tumor the thickened basement membrane of atrophic seminifer- ● Teratoma ous tubules (Figure 1) or may replace the entire tubules. ● Dermoid cyst ● The malignant germ cells have large nuclei with promi- Monodermal teratoma nent nucleoli and abundant clear cytoplasm that is rich in ● Teratoma with somatic type malignancies glycogen, demonstrable by a periodic acid–Schiff (PAS) ● Tumors of more than 1 histologic type (mixed forms) stain. Because normal germ cells are not stained with PAS, ● Mixed embryonal carcinoma and teratoma ● this stain may help to distinguish IGCNU cells from nor- Mixed teratoma and seminoma mal cells. ● Choriocarcinoma and teratoma/embryonal carcinoma ● Others Immunoprofile Most IGCNU cells stain for placental-like alkaline phos- also divided into 3 biologically distinct categories of in- phatase (PLAP)37–40 usually with a membranous and cy- fantile/prepubertal GCTs, postpubertal GCTs, and sper- toplasmic pattern. Placental-like alkaline phosphatase is matocytic seminoma. Spermatocytic seminoma is a dis- an enzyme that in addition to IGCNU is present in em- ease of elderly men and appears to have a different path- bryonal carcinoma, seminoma, and several other GCTs but ogenesis than seminoma. is usually absent in normal germ cells. The IGCNU cells Germ cell tumors have been traditionally separated into are also positive for c-Kit (CD117)41,42 and p53 but are neg- seminomatous and nonseminomatous tumors. This divi- ative for cytokeratins, human chorionic gonadotropin ␣ sion, however, is essentially for clinical purposes because (hCG), or -fetoprotein (AFP). OCT3/4, also known as of some differences in the management approach and POU5F1, is a recently recognized marker for GCTs.43 In prognosis of these 2 groups of tumors. adult testis, positive immunostaining for OCT3/4 is an indicator for the presence of IGCNU, seminoma, and/or INTRATUBULAR GERM CELL NEOPLASIA, embryonal carcinoma.44 OCT3/4 immunostain highlights UNCLASSIFIED IGCNU with a nuclear staining pattern and has proved to There is convincing evidence that intratubular germ cell be a sensitive and specific marker for detection of IGCNU 44,45 neoplasia, unclassified (IGCNU), is the precursor of all in- in biopsy specimens. D2-40, an antibody raised against vasive GCTs with the exception of spermatocytic semi- a transmembrane mucoprotein called podoplanin, stains 46–48 noma and infantile/prepubertal GCTs.21,22 Intratubular IGCNU cells (Figure 2) as well as lymphatics. There- germ cell neoplasia, unclassified, has been identified in the fore, this antibody can be used to confirm the presence or vicinity of GCTs in about 90% of cases.23,24 Additionally, absence of IGCNU adjacent to invasive GCTs and also to there is an increased prevalence of IGCNU in clinical con- highlight lymphatic invasion. ditions at risk for testicular cancer, including cryptorchi- Clinical Course and Management