TESTICULAR TUMORS: 1 GENERAL CONSIDERATIONS Since the last quarter of the 20th century, EMBRYOLOGY, ANATOMY, great advances have been made in the feld of HISTOLOGY, AND PHYSIOLOGY testicular oncology. There is now effective treat- Several thorough reviews of the embryology ment for almost all testicular germ cell tumors (22–31), anatomy (22,25,32,33), and histology (which constitute the great majority of testicular (34–36) of the testis may be consulted for more neoplasms); prior to this era, seminoma was the detailed information about these topics. only histologic type of testicular tumor that Embryology could be effectively treated after metastases had developed. The studies of Skakkebaek and his The primordial and undifferentiated gonad is associates (1–9) established that most germ cell frst detectable at about 4 weeks of gestational tumors arise from morphologically distinctive, age when paired thickenings are identifed at intratubular malignant germ cells. These works either side of the midline, between the mes- support a common pathway for the different enteric root and the mesonephros (fg. 1-1, types of germ cell tumors and reaffrms the ap- left). Genes that promote cellular proliferation proach to nomenclature of the World Health or impede apoptosis play a role in the initial Organization (WHO) (10). We advocate the use development of these gonadal ridges, includ- of a modifed version of the WHO classifcation ing NR5A1 (SF-1), WT1, LHX1, IGFLR1, LHX9, of testicular germ cell tumors so that meaningful CBX2, and EMX2 (31). At the maximum point comparisons of clinical investigations can be of their development, the gonadal, or genital, made between different institutions. ridges extend from the sixth thoracic to the Cytogenetic and molecular studies have second sacral segments of the embryo. They provided new insights into possible relation- are covered by layers of proliferated coelomic ships between different morphologic types of epithelium (fg. 1-1, right). germ cell tumors (11–21) but, from a practical By 6 weeks of development, germ cells have viewpoint, careful gross evaluation and, even migrated into the developing gonad, following more so, sound light microscopic evaluation a pathway from their initial site of formation remain the bedrocks for the assessment of these in the caudal portion of the wall of the yolk tumors, although immunohistochemistry plays sac, close to the allantois, along the wall of the a signifcant role in specifc situations. Advances hindgut and the dorsal root of the mesentery, in the feld of sex cord-stromal tumors have and from there to the adjacent gonads (fg. 1- allowed recognition of several new variants 2). Such cells are distinctive and recognizable within that group of tumors (see chapter 6), by their high content of placental-like alkaline and a number of large clinicopathologic studies phosphatase (PLAP), expression of nuclear tran- have signifcantly increased the knowledge of scription factor OCT3/4 (POU5F1) and stage- a variety of miscellaneous primary neoplasms specifc antigen 1, and abundant cytoplasmic (see chapter 7), as well as of metastatic tumors glycogen. This migration is accomplished by and hematopoietic neoplasms. There is also a amoeboid movement of the germ cells, and de- better understanding of the diverse spectrum of pends, at least in part, on transforming growth neoplasms and tumor-like lesions that affect the factor-beta and the FOXC1 gene (37,38). It is paratestis, including morphologic variants that hypothesized that the occurrence of extrago- may lead to misinterpretations. nadal germ cell tumors is explained by the 1 Tumors of the Testis and Adjacent Structures Figure 1-1 EMBRYOLOGY OF TESTIS Left: At 4 weeks of gestation, the genital ridges are apparent as mesenchymal condensations covered by coelomic epithelium that has proliferated. Right: At 6 weeks, there is ingrowth of the coelomic epithelium with extension into the mesenchyme to form the primitive sex cords. (Fig. 11-13 from Langman J. Medical embryology and human development—normal and abnormal, 2nd ed., Baltimore: Williams & Wilkins, 1969:164.) Figure 1-2 EMBRYOLOGY OF TESTIS Left: At 3 weeks of gestation, the primordial germ cells form in the wall of the yolk sac. Right: At 6 weeks, the primordial germ cells migrate to the wall of the hindgut, along the dorsal mesenteric root, and into the genital ridges. (Fig. 11-14 from Langman J. Medical embryology and human development—normal and abnormal, 2nd ed., Baltimore: Williams & Wilkins, 1969:165.) aberrant midline migration of some germ cells At 6 to 7 weeks of gestation, the prolifer- to involve such sites as the pineal region, the ated coelomic epithelium on the surface of anterior mediastinum, the sacrococcygeal area, the gonadal ridge migrates into the underlying and possibly, the retroperitoneum. mesenchyme to develop into the primitive sex 2 Testicular Tumors: General Considerations Figure 1-3 EMBRYOLOGY OF TESTIS At 8 weeks of gestation, the tunica albuginea surrounds the developing testis and the rete testis cords intermingle with mesonephric tubules at the hilum. (Fig. 11-15A from Langman J. Medical embryology and human development— normal and abnormal, 2nd ed. Baltimore: Williams & Wilkins, 1969:165.) cords (fg. 1-1, right). The molecular signals for the medulla of the testis, forming the testis, or this process appear to involve several genes, in- medullary, cords. The testis cords are, therefore, cluding GATA4, ZFPM2, and WT1+KTS, which, composed of a dual population of cells: one de- in turn, activate the SRY gene on the Y chromo- rived from the primitive sex cords and destined some, a key event for the formation of Sertoli to form the Sertoli cells of the seminiferous tu- cells and the initial molecular difference in the bules, and the second representing the migrated development of a testis as opposed to an ovary. germ cells that become the spermatogonia of Subsequently, a longitudinal groove forms be- the testis. At this stage (day 42), the anlage of tween the gonadal ridge and the more lateral the tunica albuginea is apparent at the periphery mesonephric body, resulting in a separation of of the embryonic testis as a layer of fattened these structures. At this point (approximately cells. With further development, the testis cords day 42), the developing testis becomes morpho- lose their original connection with the surface logically distinct from a developing ovary. epithelium and the tunica albuginea becomes SRY, also known as TDF (testis-determining better defned (fg. 1-3). factor), gene activation causes downstream acti- With the formation of distinct testis cords, a vation of SOX9, FGF9, and DAX1, which appear third cellular element of the developing testis to play roles in the differentiation of Sertoli cells becomes apparent as the interstitial component and their migration. This gene is also important occupying the area between the cords. The origin in the induction of the AMH (anti-müllerian of these interstitial (Leydig) cells is not entirely hormone, also known as müllerian-inhibiting clear, although a steroidogenic population of substance) gene in Sertoli cells, which produces cells appears to form along the anterior aspect of the hormone that causes regression of the mül- the mesonephros to supply both the gonad and lerian ductal system. The Sertoli cells aggregate adrenal gland, with segregation between the two around the primitive germ cells, incorporating organs perhaps mediated in part by the WNT4 them into solid tubular structures. Activation gene (31). Leydig cells become morphologically of several genes, including PDGFRA, DHH, distinct at about 8 weeks of development. They and ARX, contribute to this process and to are particularly prominent between the 4th and the formation of Leydig cells. With continued 6th months of gestation, only to regress follow- proliferation, the sex cords penetrate deep into ing birth and to reappear at puberty. 3 Tumors of the Testis and Adjacent Structures Figure 1-4 EMBRYOLOGY OF TESTIS Left: By 4 months of gestation, the rete testis cords have merged with the epigenital tubules of the mesonephros. Right: Diagram of the mature testis after descent showing the relationship of various structures. (Fig. 11-18 from Langman J. Medical embryology and human development - normal and abnormal, 2nd ed. Baltimore: Williams & Wilkins, 1969:169.) Near the hilum of the developing testis, the duce seminiferous tubules. These structures are, testis cords break up into a network of very in turn, invested by peritubular myoid cells. At small strands of cells that intermingle with this time, continuity is established between the mesonephric cells. The rete testis forms out of tubuli recti and the tubules of the rete testis. these components, although the contribution of The initially elongated confguration of the the sex cords and mesonephros to its structure developing testis becomes contracted to a more remains controversial (39). During subsequent adult-like ovoid form by about 8 weeks of ges- development, the rete testis cords merge with tation; at this time, the testis extends from the portions of the regressing mesonephric tubules, diaphragm to the site of the abdominal inguinal establishing the basis for the subsequent con- ring. During subsequent development, the testis tinuity between the seminiferous tubules and attains a position in the iliac fossa near the inter- the excretory duct of the mesonephros (wolffan nal inguinal ring until descent, which normally duct) (fg. 1-4). Continued